Production method of 1-substituted-1,2,3-triazole derivatives

ABSTRACT

A method for producing a compound of the formula:  
                 
 
     by reacting  
                 
 
     (1) in a secondary or tertiary alcohol in the presence of a base, or  
     (2) in the absence of a base is provided. According to this method, a 1-substituted-1,2,3-triazole compound having a tyrosine kinase inhibitory action can be produced efficiently in a high yield at an industrial large scale by a convenient method

TECHNICAL FIELD

[0001] The present invention relates to production methods ofintermediates for 1-substituted-1,2,3-triazole compounds having aninhibitory action on growth factor receptor tyrosine kinases (especiallyHER2) useful as pharmaceutical agents.

BACKGROUND ART

[0002] As a production method of an intermediate for a1-substituted-1,2,3-triazole compound having a tyrosine kinaseinhibitory action, for example, there is mentioned a method comprisingcondensing compound (1) of the following formula and compound (2) of thefollowing formula in the presence of a base in a solvent inert to thereaction (e.g., aromatic hydrocarbons such as benzene, toluene, xyleneetc., ethers such as tetrahydrofuran, dioxane etc., ketones such asacetone, 2-butanone etc., halogenated hydrocarbons such as chloroform,dichloromethane etc., N,N-dimethylformamide, dimethyl sulfoxide, and amixed solvent of these) to give the objective compound (3)(JP-A-11-60571, WO 98/03505):

[0003] wherein W1 is a leaving group, R⁰ is an optionally substitutedaromatic heterocyclic group, X1 is an oxygen atom, an optionallyoxidized sulfur atom, —C(═O)— or —CH(OH)—, Y₁ is CH or N, m1 is aninteger of 0 to 10, n1 is an integer of 1 to 5, the cyclic group

[0004] is an optionally substituted aromatic azole group and the ring A1may be further substituted.

[0005] In addition, as a production method of a 1-alkyl-1,2,3-triazolecompound, for example, there is mentioned a method comprising reactingthe compound (b2) of the following formula and the compound (b3) of thefollowing formula in the presence or absence of a base (JP-A-5-170763):

[0006] wherein R₁, R₂, R₃, R₄ and R₈ are the same or different and eachis a hydrogen atom or a lower alkyl group, R₂ and R₃ in combination mayform, together with the carbon atoms to which they are bonded, acyclopentane ring or a cyclohexane ring, R₅, R₆ and R₇ are the same ordifferent and each is a hydrogen atom, a halogen atom, a lower alkylgroup optionally substituted by halogen atom(s) or a lower alkoxy groupoptionally substituted by halogen atom(s), Y₂ is a halogen atom, a loweralkyl sulfonyloxy group or an aryl sulfonyloxy group, and R₉ is a 5 or6-membered heterocyclic group having 1 to 3 nitrogen atom(s), andwherein a 1H-1,2,4-triazole group is excluded and the heterocyclic groupis optionally substituted by 1 to 3, the same or different halogenatom(s), lower alkyl group(s) or lower alkoxy group(s).

[0007] The aforementioned conventional production methods pose problemsin that they show low reaction selectivity, and therefore, a low yield.A method using a silver salt of 1H-1,2,3-triazole shows fine selectivitybut requires expensive starting materials. Therefore, there is a demandfor an industrially advantageous production method of an intermediatefor a 1-substituted-1,2,3-triazole compound having an inhibitory actionon growth factor receptor tyrosine kinases (especially HER2).

[0008] As a production method for obtaining a 1,2,3-triazole compounduseful as a starting material of pharmaceutical agents or anintermediate for printing, image processing agents, by the use of ahydrazone derivative, there is known, for example, a method comprisingreacting compound (c1) of the following formula and compound (c2) underneutral or basic conditions to give compound (3) (JP-A-8-53425):

[0009] In the above formulas, R^(1c) is a lower alkyl group optionallysubstituted by halogen atom(s), a phenyl group wherein benzene ring isoptionally substituted by at least one substituent selected from halogenatom, lower alkyl group and lower alkoxy group, a benzyl group whereinbenzene ring is optionally substituted by at least one substituentselected from halogen atom, lower alkyl group and lower alkoxy group, alower alkylamino group wherein alkyl group is optionally substituted byhalogen atom, a phenylamino group wherein benzene ring is optionallysubstituted by at least one substituent selected from halogen atom,lower alkyl group and lower alkoxy group, an ammonium group that forms asalt with an inorganic acid or a carboxyl group that forms a salt withammonia; X is a halogen atom; R^(2c) and R^(3c) are each a hydrogen atomor a lower alkyl group optionally substituted by halogen atom(s); andR^(4c) is a lower alkyl group optionally substituted by halogen atom(s)or a phenyl group wherein benzene ring is optionally substituted by atleast one substituent selected from halogen atom, lower alkyl group andlower alkoxy group.

[0010] As a production method of an amine compound such as theabove-mentioned compound (c1), there is known a method comprisingreacting phthalimide butyryl chloride and chlorobenzene in the presenceof anhydrous aluminum chloride, and treating the obtained4-chloro-4-phthalimide butyrophenone with acetic acid and hydrochloricacid to give 4-chloro-4-aminobutyrophenone hydrochloride [Journal ofMedicinal Chemistry (J. Med. Chem.), vol. 9, pp. 945-949 (1966)].

[0011] The conventional production method for obtaining theaforementioned compound (c3) showed lower yield from the compound (c1).A conventional production method for obtaining an amine compound, suchas compound (c1), poses a problem in that it requires many steps.Therefore, there is a demand for an industrially advantageous productionmethod of an intermediate for a 1-substituted-1,2,3-triazole compoundhaving an inhibitory action on growth factor receptor tyrosine kinase(especially, HER2).

DISCLOSURE OF THE INVENTION

[0012] The present inventors have studied various production methods of1-substituted-1,2,3-triazole derivatives, and first found that areaction in a secondary or tertiary alcohol in the presence of a base ora reaction in the absence of a base unexpectedly results in theselective production of the objective 1-substituted-1,2,3-triazolederivative in a high yield, and that this production method is fullysatisfactory on an industrial scale, based on which they intensivelyinvestigated and completed the present invention.

[0013] They have also found that a reaction of an alkylamine compoundand a hydrazone derivative, followed by a treatment with a base,unexpectedly results in the selective production of the objective1-substituted-1,2,3-triazole derivative in a high yield, and that thisproduction method is fully satisfactory on an industrial scale, based onwhich they intensively investigated and completed the present invention.

[0014] Further, the present inventors have found that a productionmethod via a protected 4-hydroxymethyloxazole compound as anintermediate unexpectedly results in the production of the objectiveproduct in a high yield, and that this production method is fullysatisfactory on an industrial scale, based on which they intensivelyinvestigated and completed the present invention.

[0015] Accordingly, the present invention provides the following.

[0016] 1. A method for producing a compound of the formula:

[0017] wherein

[0018] R^(a1) and R^(a2) are each a hydrogen atom, a substitutedhydroxy, a substituted thiol, a substituted amino, an optionallysubstituted hydrocarbon group, an optionally substituted heterocyclicgroup or an acyl;

[0019] R^(a3) is a group of the formula:

[0020] wherein R^(a4) and R^(a5) are each a hydrogen atom, an optionallysubstituted hydroxy, an optionally substituted thiol, an optionallysubstituted amino, an optionally substituted hydrocarbon group, anoptionally substituted heterocyclic group or an acyl, or R^(a4) andR^(a5) in combination form oxo,

[0021] R^(a6) is an optionally substituted aromatic group, and

[0022] m^(a) is an integer of 0 to 10; or two or three from R^(a1),R^(a2) and R^(a3) form an optionally substituted ring, together with theadjacent carbon atom; and

[0023] R^(a7) and R^(a8) are each a hydrogen atom, a halogen, anoptionally substituted hydroxy, an optionally substituted thiol, anoptionally substituted amino, an optionally substituted hydrocarbongroup, an optionally substituted heterocyclic group or an acyl,

[0024] which method comprises reacting a compound of the formula:

[0025] wherein X^(a) is a leaving group and other symbols are as definedabove, or a salt thereof [hereinafter to be also referred briefly to ascompound (aII)] and a compound of the formula:

[0026] wherein each symbol is as defined above, or a salt thereof,

[0027] (1) in a secondary or tertiary alcohol in the presence of a base,or

[0028] (2) in the absence of a base.

[0029] 2. The production method of the aforementioned 1, which comprisesreaction in a secondary or tertiary alcohol in the presence of a base.

[0030] 3. The production method of the aforementioned 1, which comprisesreaction in a tertiary alcohol in the presence of a base.

[0031] 4. The production method of 1 above, wherein R^(a1) is a hydrogenatom.

[0032] 5. The production method of 1 above, wherein R^(a1) and R^(a2)are each a hydrogen atom.

[0033] 6. The production method of 1 above, wherein R^(a3) is a group ofthe formula:

[0034] wherein each symbol is as defined in the aforementioned 1.

[0035] 7. The production method of 6 above, wherein R^(a4) and R^(a5)are each a hydrogen atom.

[0036] 8. The production method of 6 above, wherein R^(a6) is anoptionally substituted phenyl.

[0037] 9. The production method of 6 above, wherein m^(a) is 3.

[0038] 10. The production method of 1 above, wherein R^(a7) and R^(a8)are each a hydrogen atom.

[0039] 11. A salt of a compound of the formula:

[0040] 12. A compound of the formula:

[0041] wherein X^(a′) is a halogen atom, OSO₂R^(a) or OCOR^(a) whereinR^(a) is an optionally substituted hydrocarbon group [hereinafter to bereferred to as compound (aIIa)].

[0042] 13. A method for producing compound (aIIa), which comprisesreacting a compound of the formula:

[0043] wherein M^(a) is a hydrogen atom, an alkali metal atom or analkaline earth metal atom [hereinafter to be referred to as compound(aII′)], and 1) thionyl halide [hereinafter to be referred to ascompound (aa)], 2) oxalyl halide [hereinafter to be referred to ascompound (ab)], 3) a compound of the formula:

R^(a)SO₂X^(a) or (R^(a)SO₂)₂O

[0044] wherein R^(a) is an optionally substituted hydrocarbon group andX^(a) is a leaving group [hereinafter to be referred to as compound(ac)] or 4) a compound of the formula:

R^(a)COX^(a) or (R^(a)CO)₂O

[0045] wherein R^(a) and X^(a) are as defined above [hereinafter to bereferred to as compound (ad)] under basic conditions.

[0046] 14. A compound of the formula:

[0047] or a salt thereof [hereinafter to be also referred to as compound(aIe)].

[0048] 15. The production method of the aforementioned 1 wherein R^(a1),R^(a2), R^(a7) and R^(a8) are each a hydrogen atom and R^(a3) is3-[4-(t-butoxyphenyl)]propyl.

[0049] 16. A method for producing a compound of the formula:

[0050] which comprises reacting a compound of the formula:

[0051] wherein M^(a) is a hydrogen atom, an alkaline metal atom or analkaline earth metal atom, and 1) thionyl halide, 2) oxalyl halide, 3) acompound of the formula:

R^(a)SO₂X^(a) or (R^(a)SO₂)₂O

[0052] wherein R^(a) is an optionally substituted hydrocarbon group andX^(a) is a leaving group or 4) a compound of the formula:

R^(a)COX^(a) or (R^(a)CO)₂O

[0053] wherein R^(a) and X^(a) are as defined above, under basicconditions to give a compound of the formula:

[0054] wherein X^(a′) is a halogen atom, OSO₂R^(a) or OCOR^(a) whereinR^(a) is as defined above, and reacting this compound with a compound ofthe formula:

[0055] or a salt thereof, (1) in the presence of a base in a secondaryor tertiary alcohol, or

[0056] (2) in the absence of a base to give a compound of the formula:

[0057] and deprotecting this compound.

[0058] 17. A method for producing a compound of the formula:

[0059] which comprises deprotecting a compound of the formula:

[0060] 18. A method for producing a compound of the formula:

[0061] which comprises deprotecting a compound of the formula:

[0062] 19. A method for producing a compound of the formula:

[0063] wherein R^(b1), R^(b2) and R^(b3) are each a hydrogen atom, anoptionally substituted hydroxy, an optionally substituted thiol, anoptionally substituted amino, an optionally substituted hydrocarbongroup, an optionally substituted heterocyclic group or an acyl, or twoor three from R^(b1), R^(b2) and R^(b3) form, together with the adjacentcarbon atom, an optionally substituted ring, and R^(b4) and R^(b5) areeach a hydrogen atom, an optionally substituted hydroxy, an optionallysubstituted thiol, an optionally substituted amino, an optionallysubstituted hydrocarbon group, an optionally substituted heterocyclicgroup or an acyl, and R^(b6) is an optionally substituted alkyl or anoptionally substituted phenyl, or a salt thereof [hereinafter to be alsoreferred to as compound (bI)], which comprises reacting a compound ofthe formula:

[0064] wherein each symbol is as defined above, or a salt thereof[hereinafter to be also referred to as compound (bII)] and a compound ofthe formula:

[0065] wherein X^(b1) and X^(b2) are each a halogen, and R^(b4), R^(b5)and R^(b6) are as defined above, or a salt thereof, [hereinafter also tobe referred to as compound (bIII)] and treating the reaction mixturewith a base.

[0066] 20. The production method of 19 above, wherein R^(b1) is ahydrogen atom.

[0067] 21. The production method of 19 above, wherein R^(b1) and R^(b2)are each a hydrogen atom.

[0068] 22. The production method of the aforementioned 19, whereinR^(b3) is a group of the formula:

[0069] wherein R^(b7) and R^(b8) are each a hydrogen atom, an optionallysubstituted hydroxy, an optionally substituted thiol, an optionallysubstituted amino, an optionally substituted hydrocarbon group, anoptionally substituted heterocyclic group or an acyl, or R^(b7) andR_(b8) in combination form oxo, R^(b9) is an optionally substitutedaromatic group, and m^(b) is an integer of 0 to 10.

[0070] 23. The production method of 22 above wherein R^(b7) and R^(b8)are each a hydrogen atom, R^(b9) is an optionally substituted phenyl,and m^(b) is 3.

[0071] 24. The production method of 23 above wherein R^(b1) and R^(b2)are each a hydrogen atom.

[0072] 25. The production method of 19 above wherein R^(b4) and R^(b5)are each a hydrogen atom.

[0073] 26. The production method of 19 above wherein R^(b6) is a phenylsubstituted by alkyl.

[0074] 27. A method for producing a compound of the formula:

[0075] wherein, R^(b10) is an optionally substituted amino, anoptionally substituted hydrocarbon group, an optionally substitutedheterocyclic group or an acyl, R^(b11) is a substituent, n^(b) is aninteger of 0 to 4, and R^(b12) is an optionally substituted alkylene, anoptionally substituted alkenylene or an optionally substitutedalkynylene, or a salt thereof, which comprises reacting a compound ofthe formula:

[0076] wherein each symbol is as defined above, or a salt thereof[hereinafter to be also referred to as compound (bIV)] and a compound ofthe formula:

HOOC—R^(b12)—NH₂ (bV)

[0077] wherein R^(b12) is as defined above, a salt thereof or a reactivederivative thereof [hereinafter to be also referred to as compound(bV)].

[0078] 28. A method for producing a compound of the formula:

[0079] wherein each symbol is as defined above, or a salt thereof[hereinafter to be also referred to as compound (bVII)], which comprisesreacting compound (bIV) and compound (bV), and reducing the obtainedcompound (bVI) or a salt thereof.

[0080] 29. A method for producing a compound of the formula:

[0081] wherein each symbol is as defined above, or a salt thereof[hereinafter to be also referred to as compound (bVIII)], whichcomprises reacting compound (bIV) and compound (bV), reducing theobtained compound (bVI) or a salt thereof, reacting the obtainedcompound (bVII) and compound (bIII), and treating the reaction mixturewith a base.

[0082] 30. The production method of 29 above, wherein R^(b4) and R^(b5)are each a hydrogen atom, R^(b10) is a C₁₋₃alkyl, R^(b12) is atrimethylene and n^(b) is 0.

[0083] 31. A trifluoromethanesulfonate of a compound of the formula:

[0084] wherein Rb12′ is trimethylene and other symbols are as defined inthe aforementioned 27.

[0085] 32. A method for producing a compound of the formula:

[0086] wherein Ar^(c) is an optionally substituted aromatic group,R^(c1) and R^(c2) are each a hydrogen atom or a lower alkyl, R^(c3) andR^(c4) are each a hydrogen atom or a lower alkyl, Y^(c) is C, S or SOand R^(c5) is a hydrogen atom, a lower alkyl, an optionally substitutedphenyl, an optionally substituted benzyloxy or an optionally substitutedbenzylamino, or a salt thereof [hereinafter to be also referred to ascompound (cIV)], which comprises reacting a reaction mixture of acompound of the formula:

[0087] wherein each symbol is as defined above, or a salt thereof[hereinafter to be also referred to as compound (cI)] and a compound ofthe formula:

[0088] wherein X^(c1) and X^(c2) are each a halogen, and other symbolsare as defined above, or a salt thereof [hereinafter to be also referredto as compound (cII)] with a compound of the formula:

[0089] wherein M^(c) is a hydrogen atom or a metal, and other symbolsare as defined above, or a salt thereof [hereinafter to be also referredto as compound (cIII)].

[0090] 33. The production method of 32 above, wherein Ar^(c) is4-trifluoromethylphenyl.

[0091] 34. The production method of 32 above, wherein R^(c1), R^(c2),R^(c3) and R^(c4) are each a hydrogen atom and R^(c5) is methyl.

[0092] 35. The compound (cIV) or a salt thereof.

[0093] 36. A method for producing a compound of the formula:

[0094] wherein each symbol is as defined above, or a salt thereof[hereinafter to be also referred to as compound (cVII)], which comprisessubjecting compound (cIV) to hydrolysis or catalytic reduction,subjecting the obtained compound of the formula:

[0095] wherein each symbol is as defined above, or a salt thereof[hereinafter to be also referred to as compound (cV)] to sulfonylationor halogenation, and reacting the compound with a compound of theformula:

[0096] wherein n^(c) is an integer of 1 to 10, or a salt thereof[hereinafter to be also referred to as compound (cVI)].

[0097] 37. The production method of 36 above, wherein Ar^(c) is4-trifluoromethylphenyl.

[0098] 38. The production method of 36 above, wherein R^(c1), R^(c2),R^(c3) and R^(c4) are each a hydrogen atom, R^(c5) is methyl and n^(c)is 4.

[0099] 39. A method for producing compound (cVII) or a salt thereof,which comprises reacting a reaction mixture of compound (cI) andcompound (cII) with compound (cIII), subjecting the resulting compoundto hydrolysis or catalytic reduction, subjecting the obtained compound(cV) to sulfonylation or halogenation, and reacting the compound withcompound (cVI).

[0100] 40. The production method of 39 above, wherein Ar^(c) is4-trifluoromethylphenyl.

[0101] 41. The production method of 39 above, wherein R^(c1), R^(c2),R^(c3) and R^(c4) are each a hydrogen atom, R^(c5) is methyl and n^(c)is 4.

[0102] 42. A method for producing a compound of the formula:

[0103] wherein each symbol is defined above, or a salt thereof, whichcomprises subjecting a reaction mixture of a compound of the formula:

[0104] wherein each symbol is as defined in the aforementioned 32 or asalt thereof and compound (cII) or a salt thereof to hydrolysis,subjecting the obtained compound of the formula:

[0105] wherein each symbol is as defined above or a salt thereof tosulfonylation or halogenation, and reacting the resulting compound withcompound (cVI) or a salt thereof.

[0106] 43. A method for producing compound (cVIIa) or a salt thereof,which comprises reacting a reaction mixture of compound (cIa) or a saltthereof and compound (cII) or a salt thereof with compound (cVI) or asalt thereof.

[0107] 44. A compound of the formula:

[0108] 45. A method for producing compound (cVIIa) or a salt thereof,which comprises subjecting the compound (cVa) or a salt thereof tosulfonylation or halogenation, and reacting the resulting compound withcompound (cVI) or a salt thereof.

[0109] 46.1-[4-[4-[[2-[(E)-2-[4-(Trifluoromethyl)phenyl]ethenyl]-1,3-oxazol-4-yl]methoxy]phenyl]butyl]-1H-1,2,3-triazole.

[0110] 47. The crystal of the aforementioned 46, having characteristicpeaks at diffraction angles of about 6.98, 14.02, 17.56, 21.10 and 24.70degrees in powder X-ray diffraction.

[0111] 48. A pharmaceutical composition comprising the crystal of theaforementioned 46.

BRIEF DESCRIPTION OF THE DRAWINGS

[0112]FIG. 1 is a powder X-ray diffraction chart of the compoundobtained in Reference Example 22.

[0113]FIG. 2 is a powder X-ray diffraction chart of the compoundobtained in Example 30.

DETAILED DESCRIPTION OF THE INVENTION

[0114] In this specification, the “hydrocarbon group” of the “anoptionally substituted hydrocarbon group” is exemplified by chain orcyclic hydrocarbon group (e.g., alkyl, alkenyl, alkynyl, cycloalkyl,aryl, aralkyl etc.) and the like, with preference given to chain orcyclic hydrocarbon group having 1 to 16 carbon atoms.

[0115] Examples of the “alkyl” preferably include, for example, C₁₋₆alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, tert-butyl, pentyl, hexyl etc.) and the like.

[0116] Examples of the “alkenyl” preferably include, for example, C₂₋₆alkenyl (e.g., vinyl, allyl, isopropenyl, 1-butenyl, 2-butenyl,3-butenyl, 2-methyl-2-propenyl, 1-methyl-2-propenyl, 2-methyl-1-propenyletc.) and the like.

[0117] Examples of the “alkynyl” preferably include, for example, C₂₋₆alkynyl (e.g., ethynyl, propargyl, 1-butynyl, 2-butynyl, 3-butynyl,1-hexynyl etc.) and the like.

[0118] Examples of the “cycloalkyl” preferably include, for example,C₃₋₆ cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyletc.) and the like.

[0119] Examples of the “aryl” preferably include, for example, C₆₋₁₄aryl (e.g., phenyl, 1-naphthyl, 2-naphthyl, 2-biphenylyl, 3-biphenylyl,4-biphenylyl, 2-anthryl etc.) and the like.

[0120] Examples of the “aralkyl” preferably include, for example, C₇₋₁₆aralkyl (e.g., benzyl, phenethyl, diphenylmethyl, 1-naphthylmethyl,2-naphthylmethyl, 2,2-diphenylethyl, 3-phenylpropyl, 4-phenylbutyl,5-phenylpentyl etc.) and the like.

[0121] The “substituent” of said “optionally substituted hydrocarbongroup or aromatic group” is exemplified by halogen atom (e.g., fluorine,chlorine, bromine, iodine etc.), C₁₋₃ alkylenedioxy (e.g.,methylenedioxy, ethylenedioxy etc.), nitro, cyano, optionallyhalogenated C₁₋₆ alkyl, optionally halogenated C₂₋₆ alkenyl, optionallyhalogenated C₂₋₆ alkynyl, optionally halogenated C₃₋₆ cycloalkyl,optionally substituted C₆₋₁₄ aryl, optionally halogenated C₁₋₆ alkoxy,C₁₋₆ alkoxy-carbonyl-C₁₋₆ alkoxy (e.g., ethoxycarbonylmethyloxy etc.),hydroxy, C₆₋₁₄ aryloxy (e.g., phenyloxy, 1-naphthyloxy, 2-naphthyloxyetc.), C₇₋₁₆ aralkyloxy (e.g., benzyloxy, phenethyloxy etc.), mercapto,optionally halogenated C₁₋₆ alkylthio, C₆₋₁₄ arylthio (e.g., phenylthio,1-naphthylthio, 2-naphthylthio etc.), C₇₋₁₆ aralkylthio (e.g.,benzylthio, phenethylthio etc.), amino, mono-C₁₋₆ alkylamino (e.g.,methylamino, ethylamino etc.), mono-C₆₋₁₄ arylamino (e.g., phenylamino,1-naphthylamino, 2-naphthylamino etc.), di-C₁₋₆ alkylamino (e.g.,dimethylamino, diethylamino, ethylmethylamino etc.), di-C₆₋₁₄ arylamino(e.g., diphenylamino etc.), formyl, carboxy, C₁₋₆ alkyl-carbonyl (e.g.,acetyl, propionyl etc.), C₃₋₆ cycloalkyl-carbonyl (e.g.,cyclopropylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl etc.), C₁₋₆alkoxy-carbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,tert-butoxycarbonyl etc.), C₆₋₁₄ aryl-carbonyl (e.g., benzoyl,1-naphthoyl, 2-naphthoyl etc.), C₇₋₁₆ aralkyl-carbonyl (e.g.,phenylacetyl, 3-phenylpropionyl etc.), C₆₋₁₄ aryloxy-carbonyl (e.g.,phenoxycarbonyl etc.), C₇₋₁₆ aralkyloxy-carbonyl (e.g.,benzyloxycarbonyl, phenethyloxycarbonyl etc.), 5 or 6-memberedheterocyclic carbonyl (e.g., nicotinoyl, isonicotinoyl, thenoyl, furoyl,morpholinocarbonyl, thiomorpholinocarbonyl, piperazin-1-ylcarbonyl,pyrrolidin-1-ylcarbonyl etc.), carbamoyl, mono-C₁₋₆ alkyl-carbamoyl(e.g., methylcarbamoyl, ethylcarbamoyl etc.), di-C₁₋₆ alkyl-carbamoyl(e.g., dimethylcarbamoyl, diethylcarbamoyl, ethylmethylcarbamoyl etc.),C₆₋₁₄ aryl-carbamoyl (e.g., phenylcarbamoyl, 1-naphthylcarbamoyl,2-naphthylcarbamoyl etc.), 5 or 6-membered heterocyclic carbamoyl (e.g.,2-pyridylcarbamoyl, 3-pyridylcarbamoyl, 4-pyridylcarbamoyl,2-thienylcarbamoyl, 3-thienylcarbamoyl etc.), C₁₋₆ alkylsulfonyl (e.g.,methylsulfonyl, ethylsulfonyl etc.), C₆₋₁₄ arylsulfonyl (e.g.,phenylsulfonyl, 1-naphthylsulfonyl, 2-naphthylsulfonyl etc.),formylamino, C₁₋₆ alkylcarbonylamino (e.g., acetylamino etc.), C₆₋₁₄aryl-carbonylamino (e.g., benzoylamino, naphthoylamino etc.), C₁₋₆alkoxycarbonylamino (e.g., methoxycarbonylamino, ethoxycarbonylamino,propoxycarbonylamino, butoxycarbonylamino etc.), C₁₋₆ alkylsulfonylamino(e.g., methylsulfonylamino, ethylsulfonylamino etc.), C₆₋₁₄arylsulfonylamino (e.g., phenylsulfonylamino, 2-naphthylsulfonylamino,1-naphthylsulfonylamino etc.), C₁₋₆ alkyl-carbonyloxy (e.g., acetoxy,propionyloxy etc.), C₆₋₁₄ aryl-carbonyloxy (e.g., benzoyloxy,naphthylcarbonyloxy etc.), C₁₋₆ alkoxy-carbonyloxy (e.g.,methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy,butoxycarbonyloxy etc.), mono-C₁₋₆ alkyl-carbamoyloxy (e.g.,methylcarbamoyloxy, ethylcarbamoyloxy etc.), di-C₁₋₆ alkyl-carbamoyloxy(e.g., dimethylcarbamoyloxy, diethylcarbamoyloxy etc.), C₆₋₁₄aryl-carbamoyloxy (e.g., phenylcarbamoyloxy, naphthylcarbamoyloxy etc.),nicotinoyloxy, 5 to 7-membered saturated cyclic amino (e.g.,pyrrolidin-1-yl, piperidino, piperazin-1-yl, morpholino, thiomorpholino,tetrahydroazepin-1-yl etc.), 5 to 10-membered aromatic heterocyclicgroup (e.g., 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-oxazolyl,4-oxazolyl, 5-oxazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, 2-pyridyl,3-pyridyl, 4-pyridyl, 2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl,8-quinolyl, 1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl,2-pyrazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 3-pyrrolyl, 1-imidazolyl,2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-pyridazinyl, 3-isothiazolyl,3-isooxazolyl, 1-indolyl, 2-indolyl, 3-indolyl, 2-benzothiazolyl,2-benzo[b]thienyl, 3-benzo[b]thienyl, 2-benzo[b]furanyl,3-benzo[b]furanyl etc.) and the like.

[0122] The “hydrocarbon group” may have 1 to 5, preferably 1 to 3, forexample, the above-mentioned substituents at substitutable position(s).When the number of the substituents is two or more, the respectivesubstituents may be the same or different.

[0123] The aforementioned “optionally halogenated C₁₋₆ alkyl” isexemplified by C₁₋₆ alkyl optionally having 1 to 5, preferably 1 to 3,halogen atom(s) (e.g., fluorine, chlorine, bromine, iodine etc.), suchas methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, pentyl and hexyl, and the like. Specifically, for example,methyl, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl,ethyl, 2-bromoethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, propyl,3,3,3-trifluoropropyl, isopropyl, butyl, 4,4,4-trifluorobutyl, isobutyl,sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl,5,5,5-trifluoropentyl, hexyl, 6,6,6-trifluorohexyl and the like arementioned.

[0124] As the aforementioned “optionally halogenated C₂₋₆ alkenyl”, forexample, C₂₋₆ alkenyl optionally having 1 to 5, preferably 1 to 3,halogen atom(s) (e.g., fluorine, chlorine, bromine, iodine etc.) ismentioned, such as vinyl, propenyl, isopropenyl, 2-buten-1-yl,4-penten-1-yl and 5-hexen-1-yl, and the like.

[0125] As the aforementioned “optionally halogenated C₂₋₆ alkynyl”, forexample, C₂₋₆ alkynyl optionally having 1 to 5, preferably 1 to 3,halogen atom(s) (e.g., fluorine, chlorine, bromine, iodine etc.) ismentioned, such as 2-butyn-1-yl, 4-pentyn-1-yl and 5-hexyn-1-yl), andthe like.

[0126] As the aforementioned “optionally halogenated C₃₋₆ cycloalkyl”,for example, C₃₋₆ cycloalkyl optionally having 1 to 5, preferably 1 to3, halogen atom(s) (e.g., fluorine, chlorine, bromine, iodine etc.) ismentioned, such as (cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl,and the like. Specifically, for example, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, 4,4-dichlorocyclohexyl,2,2,3,3-tetrafluorocyclopentyl, 4-chlorocyclohexyl are mentioned.

[0127] As the “C₆₋₁₄ aryl” of the aforementioned “optionally substitutedC₆₋₁₄ aryl”, for example, phenyl, 1-naphthyl, 2-naphthyl, 2-biphenylyl,3-biphenylyl, 4-biphenylyl, 2-anthryl and the like are mentioned.

[0128] As the “substituent” of the aforementioned “optionallysubstituted C₆₋₁₄ aryl”, for example, 1 to 5 from halogen, hydroxy,optionally halogenated C₁₋₆ alkyl, optionally halogenated C₁₋₆ alkoxyand the like can be mentioned.

[0129] As the aforementioned “optionally halogenated C₁₋₆ alkoxy”, forexample, C₁₋₆ alkoxy optionally having 1 to 5, preferably 1 to 3,halogen atom(s) (e.g., fluorine, chlorine, bromine, iodine etc.) ismentioned, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy,isobutoxy, sec-butoxy, pentyloxy and hexyloxy, and the like.Specifically, for example, methoxy, difluoromethoxy, trifluoromethoxy,ethoxy, 2,2,2-trifluoroethoxy, propoxy, isopropoxy, butoxy,4,4,4-trifluorobutoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy,hexyloxy and the like are mentioned.

[0130] Examples of the aforementioned “optionally halogenated C₁₋₆alkylthio” include C₁₋₆ alkylthio optionally having 1 to 5, preferably 1to 3, halogen atom(s) (e.g., fluorine, chlorine, bromine, iodine etc.)such as methylthio, ethylthio, propylthio, isopropylthio, butylthio,sec-butylthio and tert-butylthio, and the like. Specifically,methylthio, difluoromethylthio, trifluoromethylthio, ethylthio,propylthio, isopropylthio, butylthio, 4,4,4-trifluorobutylthio,pentylthio, hexylthio and the like are mentioned.

[0131] In the present specification, the “heterocyclic group” of the“optionally substituted heterocyclic group” is exemplified by amonovalent group and the like obtained by removing optional one hydrogenatom from 5 to 14-membered (monocyclic, bicyclic or tricyclic)heterocycle, preferably (i) 5 to 14-membered (preferably 5 to10-membered) aromatic heterocycle, (ii) 5 to 10-membered non-aromaticheterocycle and (iii) 7 to 10-membered crosslinked heterocycle, having,besides carbon atom, 1 or 2 kind(s) of 1 to 4 hetero atom(s) selectedfrom nitrogen atom, sulfur atom and oxygen atom.

[0132] Examples of the above-mentioned “5 to 14-membered (preferably 5to 10-membered) aromatic heterocycle” include aromatic heterocycles suchas thiophene, oxazole, triazole, benzo[b]thiophene, benzo[b]furan,benzimidazole, benzoxazole, benzothiazole, benzisothiazole,naphtho[2,3-b]thiophene, furan, pyrrole, imidazole, pyrazole, pyridine,pyrazine, pyrimidine, pyridazine, indole, isoindole, 1H-indazole,purine, 4H-quinolizidine, isoquinoline, quinoline, phthalazine,naphthyridine, quinoxaline, quinazoline, cinnoline, carbazole,β-carboline, phenanthridine, acridine, phenazine, thiazole, isothiazole,phenothiazine, isooxazole, furazan, phenoxazine and the like, and a ringformed by condensation of these rings (preferably monocycle) with 1 toseveral (preferably 1 or 2) aromatic ring(s) (e.g., benzene ring etc.)and the like.

[0133] Examples of the above-mentioned “5 to 10-membered non-aromaticheterocycle” include pyrrolidine, imidazoline, pyrazolidine, pyrazoline,piperidine, piperazine, morpholine, thiomorpholine, dioxazole,oxadiazoline, thiadiazoline, triazoline, thiadiazole, dithiazole and thelike.

[0134] Examples of the above-mentioned “7 to 10-membered crosslinkedheterocycle” include quinuclidine, 7-azabicyclo[2.2.1]heptane and thelike.

[0135] The “heterocyclic group” is preferably 5 to 14-membered(preferably 5 to 10-membered) (monocyclic or bicyclic) heterocyclicgroup having, besides carbon atom, 1 or 2 kind(s) of preferably 1 to 4hetero atom(s) selected from nitrogen atom, sulfur atom and oxygen atom.Specific examples include aromatic heterocyclic group such as 2-thienyl,3-thienyl, 2-furyl, 3-furyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl,1,2,4-triazolyl, 1,2,3-triazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl,2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 8-quinolyl,1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, 2-pyrazinyl,2-pyrimidinyl, 4-pyrimidinyl, 3-pyrrolyl, 1-imidazolyl, 2-imidazolyl,4-imidazolyl, 5-imidazolyl, 3-pyridazinyl, 3-isothiazolyl,3-isooxazolyl, 1-indolyl, 2-indolyl, 3-indolyl, 2-benzothiazolyl,2-benzo[b]thienyl, 3-benzo[b]thienyl, 2-benzo[b]furanyl,3-benzo[b]furanyl and the like, nonaromatic heterocyclic group such as1-pyrrolizinyl, 2-pyrrolizinyl, 3-pyrrolizinyl, 2-imidazolinyl,4-imidazolinyl, 2-pyrazolidinyl, 3-pyrazolidinyl, 4-pyrazolidinyl,piperidino, 2-piperidyl, 3-piperidyl, 4-piperidyl, 1-piperazinyl,2-piperazinyl, morpholino, thiomorpholino and the like, and the like.

[0136] Of these, 5 or 6-membered heterocyclic group having, besidescarbon atom, 1 to 3 hetero atom(s) selected from nitrogen atom, sulfuratom and oxygen atom is more preferable. Specifically, 2-thienyl,3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-furyl, 3-furyl, pyrazinyl,2-pyrimidinyl, 3-pyrrolyl, 3-pyridazinyl, 3-isothiazolyl, 3-isooxazolyl,1-pyrrolizinyl, 2-pyrrolizinyl, 3-pyrrolizinyl, 2-imidazolinyl,4-imidazolinyl, 2-pyrazolidinyl, 3-pyrazolidinyl, 4-pyrazolidinyl,piperidino, 2-piperidyl, 3-piperidyl, 4-piperidyl, 1-piperazinyl,2-piperazinyl, morpholino, thiomorpholino and the like are mentioned.

[0137] Examples of the “substituent” of the “optionally substitutedheterocyclic group” are similar to the “substituent” of theaforementioned “optionally substituted hydrocarbon group” and the like.

[0138] The “heterocyclic group” may have 1 to 5, preferably 1 to 3, forexample, the above-mentioned substituents at substitutable position(s).When the number of the substituents is two or more, the respectivesubstituents may be the same or different.

[0139] In the present specification, the “acyl” is exemplified by acylof the formula: —(C═O)-aR, —(C═O)—OaR, —(CαO)—NaRbR, —(C═S)—NHaR or—SO₂-cR wherein aR is hydrogen atom, optionally substituted hydrocarbongroup or optionally substituted heterocyclic group, bR is hydrogen atomor C₁₋₆ alkyl, cR is optionally substituted hydrocarbon group oroptionally substituted heterocyclic group, and the like.

[0140] The “C₁₋₆ alkyl” expressed by R^(a10) and R^(b14) is exemplifiedby methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, pentyl, hexyl and the like.

[0141] In the present specification, the “optionally substituted amino”is exemplified by (1) amino optionally having 1 or 2 substituent(s) and(2) optionally substituted cyclic amino.

[0142] The “substituent” of the “amino optionally having 1 or 2substituent(s)” of the above-mentioned (1) is exemplified by optionallysubstituted hydrocarbon group, optionally substituted heterocyclicgroup, acyl and the like.

[0143] When the number of the “substituent(s)” of the above-mentioned“amino optionally having 1 or 2 substituent(s)” is two, the respectivesubstituents may be the same or different.

[0144] The “cyclic amino” of the “optionally substituted cyclic amino”of the above-mentioned (2) is exemplified by 5 to 7-memberednon-aromatic cyclic amino having, besides one nitrogen atom and carbonatom, 1 or 2 kind(s) of 1 to 4 hetero atom(s) selected from nitrogenatom, sulfur atom and oxygen atom. Specific examples thereof includepyrrolidin-1-yl, piperidino, piperazin-1-yl, morpholino, thiomorpholino,tetrahydroazepin-1-yl, imidazolidin-1-yl, 2,3-dihydro-1H-imidazol-1-yl,tetrahydro-1(2H)-pyrimidinyl, 3,6-dihydro-1(2H)-pyrimidinyl,3,4-dihydro-1(2H)-pyrimidinyl and the like.

[0145] The “substituent” of the “optionally substituted cyclic amino” isexemplified by 1 to 3 from C₁₋₆ alkyl (e.g., methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl etc.),C₆₋₁₄ aryl (e.g., phenyl, 1-naphthyl, 2-naphthyl, 2-biphenylyl,3-biphenylyl, 4-biphenylyl, 2-anthryl etc.), C₁₋₆ alkylcarbonyl (e.g.,acetyl, propionyl etc.), 5 to 10-membered aromatic heterocyclic group(e.g., 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 1,2,4-triazolyl,1,2,3-triazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-quinolyl,3-quinolyl, 4-quinolyl, 5-quinolyl, 8-quinolyl, 1-isoquinolyl,3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, 2-pyrazinyl, 2-pyrimidinyl,4-pyrimidinyl, 3-pyrrolyl, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl,5-imidazolyl, 3-pyridazinyl, 3-isothiazolyl, 3-isooxazolyl, 1-indolyl,2-indolyl, 3-indolyl, 2-benzothiazolyl, 2-benzo[b]thienyl,3-benzo[b]thienyl, 2-benzo[b]furanyl, 3-benzo[b]furanyl etc.) and thelike.

[0146] In the present specification, the “substituted amino” isexemplified by (1) amino having 1 or 2 substituent(s) and (2)substituted cyclic amino. As the “substituent” and “cyclic amino”, the“substituent” and “cyclic amino” described in detail in theabove-mentioned (1) and (2) are shown.

[0147] In the above-mentioned formula, “aromatic group” of the“optionally substituted aromatic group” represented by Ar^(c) isexemplified by C₆₋₁₄ aryl, 5 to 14-membered aromatic heterocyclic groupand the like.

[0148] As the “C₆₋₁₄ aryl”, phenyl, naphthyl (e.g., 1-naphthyl,2-naphthyl etc.), biphenylyl (e.g., 2-biphenylyl, 3-biphenylyl,4-biphenylyl etc.), anthryl (e.g., 2-anthryl etc.) and the like areexemplified. Of these, phenyl is preferable.

[0149] The “5 to 14-membered aromatic heterocyclic group” is exemplifiedby 5 to 14-membered (preferably 5 to 10-membered) (monocyclic orbicyclic) aromatic heterocyclic group having, besides carbon atom, 1 or2 kind(s) of preferably 1 to 4 hetero atom(s) selected from nitrogenatom, sulfur atom and oxygen atom. Specific examples include thienyl(e.g., 2-thienyl, 3-thienyl), furyl (e.g., 2-furyl, 3-furyl), pyridyl(e.g., 2-pyridyl, 3-pyridyl, 4-pyridyl), quinolyl (e.g., 2-quinolyl,3-quinolyl, 4-quinolyl, 5-quinolyl, 8-quinolyl), isoquinolyl (e.g.,1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl), pyrazinyl,pyrimidinyl (e.g., 2-pyrimidinyl, 4-pyrimidinyl), pyrrolyl (e.g.,3-pyrrolyl), imidazolyl (e.g., 2-imidazolyl), pyridazinyl (e.g.,3-pyridazinyl), isothiazolyl (e.g., 3-isothiazolyl), isooxazolyl (e.g.,3-isooxazolyl), indolyl (e.g., 1-indolyl, 2-indolyl, 3-indolyl),benzothiazolyl (e.g., 2-benzothiazolyl), benzothienyl (e.g.,2-benzo[b]thienyl, 3-benzo[b]thienyl), benzofuranyl (e.g.,2-benzo[b]furanyl, 3-benzo[b]furanyl) and the like.

[0150] The “substituent” of the aforementioned “optionally substitutedC₆₋₁₄ aryl” is exemplified by 1 to 5 from halogen, hydroxy, optionallyhalogenated C₁₋₆ alkyl, optionally halogenated C₁₋₆ alkoxy and the like.

[0151] The “leaving group” represented by X^(a) is exemplified byhalogen (fluoro, chloro, bromo, iodo), alkylsulfonyloxy (e.g., C₁₋₆alkylsulfonyloxy such as methylsulfonyloxy etc.), arylsulfonyloxy (e.g.,C₆₋₁₄ arylsulfonyloxy optionally substituted by C₁₋₆ alkyl, such asp-toluenesulfonyloxy etc.) and the like.

[0152] The “substituent” of the “optionally substituted hydroxy”represented by R^(a1) and R^(a2), or R^(b1), R^(b2) and R^(b3) isexemplified by those similar to the “substituent” of the aforementioned“optionally substituted hydrocarbon group” and the like.

[0153] The “substituent” of the “optionally substituted thiol”represented by R^(a1) and R^(a2), or R^(b1), R^(b2) and R^(b3) isexemplified by those similar to the “substituent” of the aforementioned“optionally substituted hydrocarbon group” and the like.

[0154] The “substituent” of the “optionally substituted hydroxy”represented by R^(a4), R^(a5), R^(a7) and R^(a8) is exemplified by thosesimilar to the “substituent” of the aforementioned “optionallysubstituted hydrocarbon group” and the like.

[0155] The “substituent” of the “optionally substituted thiol”represented by R^(a4), R^(a5), R^(a7) and R^(a8) is exemplified by thosesimilar to the “substituent” of the aforementioned “optionallysubstituted hydrocarbon group” and the like.

[0156] The “aromatic group” of the “optionally substituted aromaticgroup” represented by R^(a6) is exemplified by C₆₋₁₄ aryl, 5 to14-membered heterocyclic group and the like.

[0157] Examples of the “C₆₋₁₄ aryl” include phenyl, 1-naphthyl,2-naphthyl, 2-anthryl and the like. Of these, phenyl is preferable.

[0158] The “5 to 14-membered heterocyclic group” is exemplified by 5 to14-membered (preferably 5 to 10-membered) (monocyclic or bicyclic)heterocyclic group having, besides carbon atom, 1 or 2 kind(s) ofpreferably 1 to 4 hetero atom(s) selected from nitrogen atom, sulfuratom and oxygen atom. Specific examples include 2-thienyl, 3-thienyl,2-furyl, 3-furyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-quinolyl,3-quinolyl, 4-quinolyl, 5-quinolyl, 8-quinolyl, 1-isoquinolyl,3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, pyrazinyl, 2-pyrimidinyl,4-pyrimidinyl, 3-pyrrolyl, 2-imidazolyl, 3-pyridazinyl, 3-isothiazolyl,3-isooxazolyl, 1-indolyl, 2-indolyl, 3-indolyl, 2-benzothiazolyl,2-benzo[b]thienyl, 3-benzo[b]thienyl, 2-benzo[b]furanyl,3-benzo[b]furanyl and the like.

[0159] The “substituent” of the “optionally substituted aromatic group”is exemplified by those similar to the “substituent” of theaforementioned “optionally substituted hydrocarbon group” and the like.

[0160] The “aromatic group” may have 1 to 5, preferably 1 to 3, forexample, the above-mentioned substituents at substitutable position(s).When the number of the substituents is two or more, the respectivesubstituents may be the same or different.

[0161] As the halogen represented by R^(a7) and R^(a8), for example,fluoro, chloro, bromo and iodo are mentioned.

[0162] As the halogen atom represented by X^(a1), for example, chloro,bromo, iodo and the like are mentioned.

[0163] As the alkaline metal atom represented by M^(a), for example,lithium, potassium, sodium and the like are mentioned, and as thealkaline earth metal, for example, calcium, magnesium and the like arementioned.

[0164] When two of R^(a1), R^(a2) and R^(a3) or two of R^(b1), R^(b2)and R^(b3) form an optionally substituted ring together with theadjacent carbon atom, the compounds (aII) and (bII) are, for example,represented by the formula:

[0165] wherein A ring is an optionally substituted ring, R¹ is R^(a1) orR^(b1), and X is X^(a) or —NH₂.

[0166] When three of R^(a1), R^(a2) and R^(a3) or three of R^(b1),R^(b2) and R^(b3) form an optionally substituted ring together with theadjacent carbon atom, the compounds (aII) and (bII) are represented bythe formula:

[0167] wherein B ring is an optionally substituted ring and other symbolis as defined above.

[0168] The “ring” of the “optionally substituted ring” formed by two orthree of R^(a1), R^(a2) and R^(a3) and two or three of R^(b1), R^(b2)and R^(b3) is exemplified by 3 to 8-membered homocyclic ring orheterocyclic ring and the like.

[0169] As the “3 to 8-membered homocyclic ring”, for example, C₃₋₈cycloalkane such as cyclopropane, cyclobutane, cyclopentane, cyclohexaneand the like, C₃₋₈ cycloalkene such as cyclopropene, cyclobutene,cyclopentene, cyclohexene and the like, C₃₋₈ cycloalkyne such ascycloheptyne, cyclooctyne and the like, benzene and the like arementioned.

[0170] As the “3 to 8-membered heterocyclic”, for exemple, 3 to8-membered heterocyclic, such as aziridine, azetidine, morpholine,thiomorpholine, piperazine, piperidine, pyrrolidine, hexamethylenimine,heptamethylenimine, hexahydropyrimidine, pyridine, pyrimidine, oxazole,thiazole, quinoline, benzothiophene and the like are mentioned.

[0171] The “substituent” of the “optionally substituted ring” isexemplified by those similar to the “substituent” of the aforementioned“optionally substituted hydrocarbon group” and the like.

[0172] The “ring” may have 1 to 5, preferably 1 to 3, for example, theabove-mentioned substituents at substitutable position(s). When thenumber of the substituents is two or more, the respective substituentsmay be the same or different.

[0173] The “halogen” represented by X^(b1) and X^(b2) is exemplified byfluoro, chloro, bromo and iodo.

[0174] The “substituent” of the “optionally substituted hydroxy”represented by R^(b4), R^(b5), R^(b7) and R^(b8) is exemplified by thosesimilar to the “substituent” of the aforementioned “optionallysubstituted hydrocarbon group” and the like.

[0175] The “substituent” of the “optionally substituted thiol”represented by R^(b4), R^(b5), R^(b7) and R^(b8) is exemplified by thosesimilar to the “substituent” of the aforementioned “optionallysubstituted hydrocarbon group” and the like.

[0176] The “alkyl” of the “optionally substituted alkyl” represented byR^(b6) is exemplified by C₁₋₆ alkyl (e.g., methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl etc.)and the like.

[0177] The “substituent” of the “optionally substituted alkyl” isexemplified by 1 to 5 from those similar to the “substituent” of theaforementioned “optionally substituted hydrocarbon group” and the like.

[0178] The “substituent” of the “optionally substituted phenyl”represented by R^(b6) is exemplified by 1 to 5 from those similar to the“substituent” of the aforementioned “optionally substituted hydrocarbongroup” and the like.

[0179] The “aromatic group” of the “optionally substituted aromaticgroup” and “optionally substituted aromatic group” represented by R^(b9)is exemplified by C₆₋₁₄ aryl, 5 to 14-membered heterocyclic group andthe like.

[0180] The “C₆₋₁₄ aryl” is exemplified by phenyl, 1-naphthyl,2-naphthyl, 2-biphenylyl, 3-biphenylyl, 4-biphenylyl, 2-anthryl and thelike. Of these, phenyl is preferable.

[0181] The “5 to 14-membered heterocyclic group” is exemplified by 5 to14-membered (preferably 5 to 10-membered) (monocyclic or bicyclic)heterocyclic group having, besides carbon atom, 1 or 2 kind(s) ofpreferably 1 to 4 hetero atom(s) selected from nitrogen atom, sulfuratom and oxygen atom. Specific examples include 2-thienyl, 3-thienyl,2-furyl, 3-furyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-quinolyl,3-quinolyl, 4-quinolyl, 5-quinolyl, 8-quinolyl, 1-isoquinolyl,3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, pyrazinyl, 2-pyrimidinyl,4-pyrimidinyl, 3-pyrrolyl, 2-imidazolyl, 3-pyridazinyl, 3-isothiazolyl,3-isooxazolyl, 1-indolyl, 2-indolyl, 3-indolyl, 2-benzothiazolyl,2-benzo[b]thienyl, 3-benzo[b]thienyl, 2-benzo[b]furanyl,3-benzo[b]furanyl and the like.

[0182] The “substituent” of the “optionally substituted aromatic group”is exemplified by those similar to the “substituent” of theaforementioned “optionally substituted hydrocarbon group” and the like.

[0183] The “aromatic group” may have 1 to 5, preferably 1 to 3, forexample, the above-mentioned substituents at substitutable position(s).When the number of the substituents is two or more, the respectivesubstituents may be the same or different.

[0184] The “substituent” represented by R^(b11) is exemplified by thosesimilar to the “substituent” of the aforementioned “optionallysubstituted hydrocarbon group” and the like.

[0185] The “alkylene” of the “optionally substituted alkylene”represented by R^(b12) is exemplified by C₁₋₁₀ alkylene such as —CH₂—,—(CH₂)₂-, —(CH₂)₃-, —(CH₂)₄-, —(CH₂)₅-, —(CH₂)₆-, —(CH₂)₇-, —(CH₂)₈- andthe like.

[0186] The “substituent” of the “optionally substituted alkylene” isexemplified by 1 to 5, preferably 1 to 3, from those similar to the“substituent” of the aforementioned “optionally substituted hydrocarbongroup” and the like. When the number of the substituents is two or more,the respective substituents may be the same or different.

[0187] The “alkenylene” of the “optionally substituted alkenylene”represented by R^(b12) is exemplified by C₂₋₁₀ alkenylene such as—CH═CH—, —CH₂—CH═CH—, —CH₂—CH═CH—CH₂—, —CH₂—CH₂—CH═CH—, —CH═CH—CH═CH—,—CH═CH—CH₂—CH₂—CH₂-, —CH═CH—CH═CH—CH₂—CH₂-, —CH═CH—CH═CH—CH═CH—,—CH═CH—CH—CH—CH₂—CH₂—CH₂-, —CH═CH—CH═CH—CH₂—CH₂—CH₂-,—CH═CH—CH═CH—CH═CH—CH₂-, —CH═CH—CH—CH—CH₂—CH₂—CH₂—CH₂-,—CH═CH—CH═CH—CH₂—CH₂—CH₂—CH₂-, —CH═CH—CH═CH—CH═CH—CH₂—CH₂-,—CH═CH—CH═CH—CH═CH—CH═CH— and the like.

[0188] The “substituent” of the “optionally substituted alkenylene” isexemplified by 1 to 5, preferably 1 to 3, from those similar to the“substituent” of the aforementioned “optionally substituted hydrocarbongroup” and the like. When the number of the substituents is two or more,the respective substituents may be the same or different.

[0189] The “alkynylene” of the “optionally substituted alkynylene”represented by R^(b12) is exemplified by C₂₋₁₀ alkynylene such as

—C≡C—, —CH₂—C≡C—, —CH₂—C≡C—CH₂—CH_(2—)

[0190] and the like.

[0191] The “substituent” of the “optionally substituted alkynylene” isexemplified by 1 to 5, preferably 1 to 3, from those similar to the“substituent” of the aforementioned “optionally substituted hydrocarbongroup” and the like. When the number of the substituents is two or more,the respective substituents may be the same or different.

[0192] The “aromatic group” may have 1 to 5, preferably 1 to 3, forexample, the above-mentioned substituents at substitutable position(s).When the number of the substituents is two or more, the respectivesubstituents may be the same or different.

[0193] The “lower alkyl” represented by R^(c1), R^(c2), R^(c3), R^(c4)and R^(c5) is exemplified by C₁₋₆ alkyl (e.g., methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl etc.)and the like.

[0194] The “substituent” of the “optionally substituted phenyl”,“optionally substituted benzyloxy” and “optionally substitutedbenzylamino”, represented by R^(c5) is exemplified by 1 to 5, preferably1 to 3, from the “substituent” of the optionally substituted aromaticgroup represented by Ar^(c) and the like. When the number of thesubstituents is two or more, the respective substituents may be the sameor different.

[0195] The “halogen” represented by X^(c1) and X^(c2) is exemplified byfluorine, chlorine, bromine, iodine and the like.

[0196] The “metal” represented by M^(c) is exemplified by alkali metal(e.g., lithium, sodium, potassium etc.), alkaline earth metal (e.g.,magnesium, calcium etc.) and the like.

[0197] The reactive derivative of carboxylic acid is exemplified by acidhalide (acetyl chloride, acetyl bromide etc.), acid anhydride (aceticanhydride etc.), and the like.

[0198] R^(a1) is preferably hydrogen atom.

[0199] It is more preferable that R^(a1) and R^(a2) be hydrogen atoms.

[0200] R^(a3) is preferably a group of the formula:

[0201] wherein each symbol is as defined above.

[0202] More preferably, R^(a4) and R^(a5) are hydrogen atoms.

[0203] R^(a6) is preferably phenyl optionally having substituent(s)(preferably C₁₋₆ alkoxy, particularly tert-butoxy).

[0204] m^(a) is preferably 3 or 4.

[0205] R^(a7) is preferably hydrogen atom.

[0206] R^(a8) is preferably hydrogen atom.

[0207] R^(b1) is preferably hydrogen atom.

[0208] It is more preferable that R^(b1) and R^(b2) be hydrogen atoms.

[0209] R^(b3) is preferably a group of the formula:

[0210] wherein each symbol is as defined above.

[0211] More preferably, R^(b7) and R^(b8) are hydrogen atoms.

[0212] R^(b9) is preferably phenyl optionally having substituent(s)(preferably C₁₋₆ alkoxy).

[0213] m^(b) is preferably 3.

[0214] R^(b4) and R^(b5) are preferably hydrogen atoms.

[0215] R^(b6) is preferably phenyl optionally having substituent(s)(preferably alkyl).

[0216] R^(b10) is preferably optionally substituted hydrocarbon group(preferably alkyl), more preferably C₁₋₃ alkyl.

[0217] n^(b) is preferably 0.

[0218] R^(b12) is preferably optionally substituted alkylene, morepreferably trimethylene.

[0219] Ar^(c) is preferably optionally substituted phenyl, morepreferably 4-trifluoromethylphenyl.

[0220] R^(c1) is preferably hydrogen atom.

[0221] R^(c2) is preferably hydrogen atom.

[0222] R^(c3) is preferably hydrogen atom.

[0223] R^(c4) is preferably hydrogen atom.

[0224] Y^(c) is preferably carbon atom.

[0225] M^(c) is preferably alkali metal (e.g., lithium, sodium,potassium etc.).

[0226] R^(c5) is preferably lower alkyl, more preferably methyl.

[0227] n^(c) is preferably 4.

[0228] The compound (cIV) is a novel compound, which is specificallyexemplified by4-(acetoxymethyl)-2-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]-1,3-oxazoleand a salt thereof.

[0229] The salts of the compounds represented by the formulas (aIa),(aIb), (bI), (cI)-(cVII), (cIa), (cVa), (cVIIa) and the like in thespecification are preferably pharmacologically acceptable salts, whichare exemplified by salts with inorganic acids, salts with organic acids,salts with inorganic base, salts with organic base and the like.

[0230] Examples of the salts with inorganic acid include salts withhydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid,phosphoric acid and the like.

[0231] Examples of the salts with organic acid include salts with formicacid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid,tartaric acid, maleic acid, citric acid, succinic acid, malic acid,methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid andthe like.

[0232] Examples of the salts with inorganic base include alkali metalsalt such as sodium, potassium salt and the like; alkaline earth metalsalt such as calcium salt, magnesium salt and the like; ammonium saltand the like.

[0233] Examples of the salts with organic base include salts withtrimethylamine, triethylamine, pyridine, picoline, ethanolamine,diethanolamine, triethanolamine, dicyclohexylamine,N,N′-dibenzylethylenediamine and the like.

[0234] The production methods of compounds (aIa) and (aIb) useful as anintermediate for a 1-substituted-1,2,3-triazole compound having aninhibitory action on tyrosine kinases (especially HER2) are shown in thefollowing.

[0235] When the compound (aII) and compound (aIII) are on the market,commercially available products thereof may be used as they are, orcompound (aII) and compound (aIII) may be produced according to a methodknown per se, a method analogous thereto, and the like.

[0236] wherein each symbol is as defined above.

[0237] (Reaction a1)

[0238] The compound (aII) and compound (aIII) are reacted in secondaryor tertiary alcohol in the presence of a base to give compound (aIa) or(aIb).

[0239] The amount of use of compound (aIII) is about 0.1-10 mol,preferably about 0.5-3.0 mol, per 1 mol of compound (aII).

[0240] The amount of use of the base is about 0.1-10 mol, preferablyabout 0.5-3.0 mol, per 1 mol of compound (aII).

[0241] Examples of the “base” include hydride of alkali metal oralkaline earth metal (e.g., lithium hydride, sodium hydride, potassiumhydride, calcium hydride etc.), amide of alkali metal or alkaline earthmetal (e.g., lithium amide, sodium amide, lithium diisopropylamide,lithium dicyclohexylamide, lithium hexamethyl disilazide, sodiumhexamethyl disilazide, potassium hexamethyl disilazide etc.), hydroxideof alkali metal or alkaline earth metal (e.g., sodium hydroxide,potassium hydroxide, lithium hydroxide, calcium hydroxide etc.), metalhydrocarbon (e.g., butyllithium, tert-butyllithium etc.), lower alkoxideof alkali metal or alkaline earth metal (e.g., sodium ethoxide, sodiumethoxide, potassium tert-butoxide etc.), carbonate of alkali metal oralkaline earth metal (e.g., sodium hydrogen carbonate, sodium carbonate,potassium carbonate etc.), organic base [amines (e.g., triethylamine,diisopropylethylamine, N-methylmorpholine, dimethylaminopyridine, DBU(1,8-diazabicyclo[5.4.0]undec-7-ene), DBN(1,5-diazabicyclo[4.3.0]non-5-ene) etc.), organic base of basicheterocyclic compound (e.g., pyridine, imidazole, 2,6-lutidine etc.)etc.], and the like. Of these, hydroxide of alkali metal or alkalineearth metal is preferable.

[0242] Examples of the “secondary or tertiary alcohol” include secondaryalcohol such as isopropyl alcohol, 2-butanol etc., tertiary alcohol suchas tert-butanol, 2-methyl-2-butanol etc., and the like. Of these,tertiary alcohol is preferable.

[0243] This reaction may be carried out in a solvent inert to thereaction, besides secondary or tertiary alcohol. Examples of the “inertsolvent” include halogenated hydrocarbons (e.g., dichloromethane,chloroform, 1,2-dichloroethane, carbon tetrachloride etc.), aromatichydrocarbons (e.g., benzene, toluene, xylene, chlorobenzene etc.),ethers (e.g., diethyl ether, diisopropy ether, tert-butylmethyl ether,diphenyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, diglymeetc.), aliphatic hydrocarbons (e.g., hexane, pentane, cyclohexane etc.),amides (e.g., N,N-dimethylformamide, N,N-dimethylacetamide,1-methyl-2-pyrrolidone, hexamethylphosphoric triamide etc.), sulfoxides(e.g., dimethyl sulfoxide etc.), primary alcohols (e.g., methanol,ethanol), nitriles (e.g., acetonitrile, propionitrile etc.), water, amixture of two or more thereof and the like.

[0244] This reaction is carried out in the presence of an inorganic salt(e.g., halogenated alkali metal salt such as sodium iodide, sodiumbromide, potassium iodide, potassium bromide etc.), where necessary.

[0245] The reaction temperature is generally from about 0° C. to 150°C., preferably from about 20° C. to 130° C. The reaction time isgenerally about 0.5 hour to 100 hours, preferably about 1 hour to 20hours.

[0246] The compound (aIa) or (aIb) thus obtained can be isolated andpurified from a reaction mixture by a known method, such asconcentration, concentration under reduced pressure, solvent extraction,crystallization, recrystallization, phase transfer, chromatography andthe like.

[0247] For example, a method comprising addition of an acid after theabove-mentioned reaction, and isolation and purification to give a saltof compound (aIa) or (aIb) is preferably mentioned. Examples of the“acid” include mineral acids such as hydrochloric acid, hydrobromicacid, sulfuric acid etc., organic acids such as acetic acid,trifluoroacetic acid, tartaric acid, maleic acid, citric acid,methanesulfonic acid, p-toluenesulfonic acid etc., and the like. Theamount of use of the “acid” is about 0.3-5.0 mol, preferably about0.8-1.5 mol, per 1 mol of compound (aII).

[0248] (Reaction a2)

[0249] The compound (aII) and compound (aIII) are reacted in the absenceof a base to give compound (aIa) or (aIb).

[0250] The amount of use of compound (aIII) is about 0.1-100 mol,preferably about 0.5-5 mol, per 1 mol of compound (aII).

[0251] This reaction is carried out in the presence of a solvent inertto the reaction. Examples of the “inert solvent” include halogenatedhydrocarbons (e.g., dichloromethane, chloroform, 1,2-dichloroethane,carbon tetrachloride etc.), aromatic hydrocarbons (e.g., benzene,toluene, xylene, chlorobenzene etc.), ethers (e.g., diglyme, diethylether, diisopropy ether, tert-butylmethyl ether, diphenyl ether,tetrahydrofuran, dioxane, 1,2-dimethoxyethane etc.), aliphatichydrocarbons (e.g., hexane, pentane, cyclohexane etc.), amides (e.g.,N,N-dimethylformamide, N,N-dimethylacetamide, 1-methyl-2-pyrrolidone,hexamethylphosphoric triamide etc.), sulfoxides (e.g., dimethylsulfoxide etc.), alcohols (e.g., methanol, ethanol, isopropyl alcohol,2-butanol, tert-butanol, 2-methyl-2-butanol etc.), nitrites (e.g.,acetonitrile, propionitrile etc.), water, a mixture of two or morethereof and the like. Of these, toluene, diglyme, N,N-dimethylformamide,dimethyl sulfoxide, 2-butanol, 2-methyl-2-butanol and the like arepreferable.

[0252] Where necessary, this reaction is carried out in the presence ofan inorganic salt (e.g., halogenated alkali metal salt such as sodiumiodide, sodium bromide, potassium iodide, potassium bromide etc.).

[0253] The reaction temperature is generally from about 0° C. to 150°C., preferably from about 20° C. to 130° C. The reaction time isgenerally about 0.5 hour to 100 hours, preferably about 1 hour to 50hours.

[0254] The compound (aIa) or (aIb) thus obtained can be isolated andpurified from a reaction mixture by a known method, such asconcentration, concentration under reduced pressure, solvent extraction,crystallization, recrystallization, phase transfer, chromatography andthe like.

[0255] For example, a method comprising addition of an acid after theabove-mentioned reaction, and isolation and purification to give a saltof compound (aIa) or (aIb) is preferably mentioned. Examples of the“acid” include mineral acids such as hydrochloric acid, hydrobromicacid, sulfuric acid etc., organic acids such as acetic acid,trifluoroacetic acid, tartaric acid, maleic acid, citric acid,methanesulfonic acid, p-toluenesulfonic acid etc., and the like. Theamount of use of the “acid” is about 0.3-5.0 mol, preferably about0.8-1.5 mol, per 1 mol of compound (aII).

[0256] Of the compounds (aIa) and (aIb), a salt of the compound of theformula

[0257] is novel. Examples of the “salt” include those similar to thesalt of a compound of the above-mentioned formula (aIa). Of those, acidaddition salts such as hydrochloride, methanesulfonic acid salt and thelike are preferable.

[0258] Of the compounds (aIa) and (aIb), a compound of the formula (aIe)and a salt thereof are novel. Examples of the salt include those similarto the salt of a compound of the above-mentioned formula (aIa).

[0259] By deprotection of compound (aIe), a compound of the formula:

[0260] and a salt thereof can be produced. Examples of the salt includethose similar to the salt of a compound of the above-mentioned formula(aIa). This deprotection can be carried out under mild conditions fromamong the general means of deprotecting protected hydroxy group, and isindustrially advantageous. For example, compound (aIe) is reacted in thepresence of an acid to remove t-butyl, which is a hydroxy protectinggroup according to a conventional method for deprotection. Examples ofthe “acid” include organic acids such as acetic acid, trifluoroaceticacid, trichloroacetic acid, tartaric acid, maleic acid, citric acid,methanesulfonic acid, toluenesulfonic acid and the like, and mineralacids such as sulfuric acid, hydrochloric acid, hydrobromic acid,chloric acid, perchloric acid, bromic acid, perbromic acid, iodic acid,periodic acid and the like. The solvent may be or may not be used. Theacid may be or may not be diluted. When it is to be diluted, it ispreferably diluted to 0.01 N-5 N. The reaction temperature is generallyfrom 0° C. to 100° C., preferably from 20° C. to 70° C. The reactiontime is generally about 0.1 hour to 5 hours, preferably about 0.1 hourto 2 hours.

[0261] The compound (aIe) can be produced by reacting, from among thecompounds (aII), a compound [compound (aIIa)] wherein R^(a1) and R^(a2)are both hydrogen atoms and R^(a3) is 3-[4-(tert-butoxyphenyl)]-propyland triazole.

[0262] The compound (aIIa) can be produced by, for example, reactingcompound (aII′) and compound (aa), (ab) or (ac) under basic conditions.That is, by reacting compound (aII′) and compound (aa) or (ab), acompound wherein X^(a′) is halogen can be produced from among thecompounds (aIIa), and by reacting compound (aII′) and compound (ac), acompound wherein X^(a′) is OSO₂R^(a) can be produced from among thecompounds (aIIa), and by reacting compound (aII′) and compound (ad), acompound wherein X^(a′) is OCOR^(a) can be produced from among thecompounds (aIIa). These reactions are all carried out under basicconditions. When a compound wherein M^(a) is alkaline metal atom oralkaline earth metal atom is used as compound (aII′), a base does notneed to be added, because they are basic, but when a compound whereinM^(a) is hydrogen atom is used as compound (II^(a′)), a base isgenerally added to the reaction mixture. Examples of the preferable“base” include tertiary amines such as trimethylamine, triethylamine,1,8-diazabicyclo[5.4.0]-7-undecene etc., heterocyclic aromatic organicbases such as pyridine, picoline etc. and the like.

[0263] When compound (aII′) and compound (aa) or (ab) are reacted, thereaction generally proceeds in a solvent inert to the reaction underbasic conditions. Alternatively, the “base” may be used as a solvent.Examples of the “solvent” include halogenated hydrocarbons such asdichloromethane, dichloroethane and the like, aromatic hydrocarbons suchas benzene, toluene, xylene and the like, ethers such as diethyl ether,diisopropy ether, tert-butylmethyl ether, tetrahydrofuran and the like,nitriles such as acetonitrile, propionitrile, isopropionitrile and thelike, and esters such as ethyl acetate, isopropyl acetate and the like.The reaction temperature is generally from 0° C. to 100° C., preferably10° C. to 70° C.

[0264] The compound (aII′) and compound (ac) or (ad) can be reactedaccording to a conventional method, which proceeds in an organic solventgenerally inert to the reaction under basic conditions. Alternatively,the “base” may be used as a solvent. Examples of the “organic solventinert to the reaction” include halogenated hydrocarbons such asdichloromethane, dichloroethane and the like, aromatic hydrocarbons suchas benzene, toluene, xylene and the like, ethers such as diethyl ether,diisopropy ether, tert-butylmethyl ether, tetrahydrofuran and the like,nitriles such as acetonitrile, propionitrile, isopropionitrile and thelike, esters such as ethyl acetate, isopropyl acetate and the like, andthe like. The reaction is generally carried out by cooling a solutioncontaining compound (aII′) to a temperature of not more than 10° C.,adding dropwise compound (aa) thereto with stirring and reacting themixture at 5-20° C. for 10 min-6 hours.

[0265] Of the compounds (aIIa), a compound wherein X^(a′) is OSO₂R^(a)or OCOR^(a) is further reacted with halogen compound to produce acompound wherein X^(a,) is halogen from among the compounds (aIIa).

[0266] By reacting halogen compound with sulfonyloxy compound [compoundwherein X^(a,) is OSO₂R^(a) in the formula (aIIa)] produced by reactingthe above-mentioned (aII′) and compound (ac), a compound wherein X^(a′)is halogen in the formula (aIIa) can be produced. Generally, theabove-mentioned sulfonyloxy compound is reacted with halogen compound[e.g., alkali halide (e.g., sodium chloride, potassium chloride, sodiumbromide, potassium bromide, sodium iodide, potassium iodide etc.),pyridinium halide (pyridinium chloride, pyridinium bromide, pyridiniumiodide etc.), hydrogen halide (e.g., hydrochloric acid, hydrobromicacid, hydriodic acid etc.), hydrogen halide salt of tertiary amine(e.g., trimethylamine hydrochloride, trimethylamine hydrobromide,triethylamine hydrochloride, triethylamine hydrobromide etc.) and thelike] in a solvent in the presence of a base [inorganic base (e.g.,alkali metal such as sodium, potassium etc.; alkaline earth metal suchas calcium, magnesium etc.; hydroxide such as ammonium etc.) or anorganic base (e.g., trimethylamine, triethylamine, pyridine, picolineetc.)]. Alternatively, by reacting compound (aII′) and a compound,wherein X is OSO₂R^(a) from among the compounds (ac), and then reactingthe resulting compound with halogen compound, compound (aIIa) whereinX^(a′) is halogen can be also produced. The solvent only needs to beinert. Examples thereof include chain or cyclic ethers such as diethylether, diisopropy ether, tert-butylmethyl ether, tetrahydrofuran and thelike, chain alcohols having 1 to 5 carbon atoms, such as methanol,ethanol, isopropyl alcohol and the like, ketones such as acetone,2-butanone, 2-pentanone, 3-pentanone and the like, ethers such asdiethyl ether, diisopropy ether, tert-butylmethyl ether, tetrahydrofuranand the like, nitrites such as acetonitrile, propionitrile,isopropionitrile and the like, esters such as ethyl acetate, isopropylacetate and the like, amides such as N,N-dimethylacetamide,N,N-dimethylacetamide, N-methylpyrrolidone and the like, and the like.Alternatively, the “base” may be used alone as a solvent. The reactiontemperature is from room temperature to the boiling point of thesolvent, preferably from 25° C. to the boiling point of the solvent. Thereaction can be generally terminated upon confirmation of decrease inthe starting materials by a typical analytical method.

[0267] The compound (aIIa) obtained in this way is novel.

[0268] Of the compounds (aIa) and (aIb), for example, a compound of theformula

[0269] wherein R^(a1a), R^(a2a), R^(a4a) and R^(a5a) are each a hydrogenatom, R^(a6a) is phenyl having (i) optionally substituted hydroxy or(ii) optionally substituted thiol as a substituent, and other symbolsare as defined above, and a salt thereof can be converted to a1-substituted-1,2,3-triazole compound useful as a pharmaceutical agentand the like, according to a method known per se, such as a methoddescribed in JP-A-11-60571 or a method analogous thereto.

[0270] The “optionally substituted hydroxy” of the “phenyl substitutedby optionally substituted hydroxy” represented by R^(a6a) is exemplifiedby those similar to the aforementioned “optionally substituted hydroxy”represented by R^(a4) or R^(a5).

[0271] The “optionally substituted thiol” of the “phenyl substituted byoptionally substituted thiol” represented by R^(a6a) is exemplified bythose similar to the aforementioned “optionally substituted thiol”represented by R^(a4) or R^(a5)R^(a8).

[0272] For example, compound (aIc) or (aId) is subjected to deprotectionknown per se, where necessary, then reacted with a compound of theformula

R^(a12)-(CH₂)_(qa)-W^(a)

[0273] wherein R^(a12) is an optionally substituted aromaticheterocyclic group, qa is an integer of 1 to 5, and W^(a) is a leavinggroup, or a salt thereof [hereinafter to be briefly referred to ascompound (aIV)] to give a compound of the formula

[0274] wherein X^(a1) is an oxygen atom or a sulfur atom, and othersymbols are as defined above, or a salt thereof.

[0275] When the compound (aIV) is on the market, a commerciallyavailable product thereof may be used as it is, or compound (aIV) may beproduced according to a method known per se, a method analogous thereto,and the like.

[0276] The “leaving group” represented by W^(a) is exemplified by thosesimilar to the “leaving group” represented by X^(a) and the like.

[0277] The “aromatic heterocyclic group” of the “optionally substitutedaromatic heterocyclic group” represented by R^(a12) is exemplified by 5to 14-membered (preferably 5 to 10-membered) (monocyclic or bicyclic)heterocyclic group, having, besides carbon atom, 1 or 2 kind(s) ofpreferably 1 to 4 hetero atom(s) selected from nitrogen atom, sulfuratom and oxygen atom. Examples thereof include 2-thienyl, 3-thienyl,2-furyl, 3-furyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 1,2,4-triazolyl,1,2,3-triazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-quinolyl,3-quinolyl, 4-quinolyl, 5-quinolyl, 8-quinolyl, 1-isoquinolyl,3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, 2-pyrazinyl, 2-pyrimidinyl,4-pyrimidinyl, 3-pyrrolyl, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl,5-imidazolyl, 3-pyridazinyl, 3-isothiazolyl, 3-isooxazolyl, 1-indolyl,2-indolyl, 3-indolyl, 2-benzothiazolyl, 2-benzo[b]thienyl,3-benzo[b]thienyl, 2-benzo[b]furanyl, 3-benzo[b]furanyl and the like.Preferred is oxazolyl such as 2-oxazolyl, 4-oxazolyl, 5-oxazolyl and thelike.

[0278] The “substituent” of the “optionally substituted aromaticheterocyclic group” represented by R^(a12) is exemplified by 1 to 5 from“optionally substituted hydroxy”, “optionally substituted thiol”,“optionally substituted amino”, “optionally substituted hydrocarbongroup”, “optionally substituted heterocyclic group” and “acyl”represented by R^(a4) and R^(a5). Of these, optionally substitutedhydrocarbon group is preferable and C₂₋₆ alkenylene substituted byoptionally substituted C₆₋₁₄ aryl is more preferable.

[0279] (Reaction b1)

[0280] wherein each symbol is as defined above.

[0281] The compound (bII) and compound (bIII) are reacted and thereaction mixture is treated with a base to give compound (bI).

[0282] When the compound (bII) is on the market, a commerciallyavailable product thereof may be used as it is, or compound (bII) may beproduced according to a method known per se, a method analogous thereto,the method of Reaction B to be mentioned later and the like.

[0283] When the compound (bIII) is on the market, a commerciallyavailable product thereof may be used as it is, or compound (bIII) maybe produced according to a method known per se, a method analogousthereto, and the like.

[0284] The amount of use of compound (bIII) is about 0.1-10 mol,preferably about 0.5-3.0 mol, per 1 mol of compound (bII).

[0285] The reaction of compound (bII) and compound (bIII) is preferablycarried out in a solvent inert to the reaction. Examples of the “inertsolvent” include halogenated hydrocarbons (e.g., dichloromethane,chloroform, 1,2-dichloroethane, carbon tetrachloride etc.), aromatichydrocarbons (e.g., benzene, toluene, xylene, chlorobenzene etc.),ethers (e.g., diethyl ether, diisopropy ether, tert-butylmethyl ether,diphenyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane etc.),aliphatic hydrocarbons (e.g., hexane, pentane, cyclohexane etc.),alcohols (e.g., methanol, ethanol, isopropylalcohol, 2-butanol,tert-butanol, 2-methyl-2-butanol etc.), amides (e.g.,N,N-dimethylformamide, N,N-dimethylacetamide, 1-methyl-2-pyrrolidone,hexamethylphosphoric triamide etc.), sulfoxides (e.g., dimethylsulfoxide etc.), nitriles (e.g., acetonitrile, propionitrile etc.),water, a mixture of two or more thereof and the like. Of these, methanolis preferable.

[0286] The reaction temperature is generally from about 0° C. to 150°C., preferably from about 10 to 80° C. The reaction time is generallyfrom about 0.2 hour to 20 hours, preferably from about 0.5 hour to 3hours.

[0287] Then the reaction mixture is treated with a base to give compound(bI).

[0288] The treatment with a base generally includes mixing the reactionmixture with a base, or concentration of the reaction mixture followedby mixing of the concentrate with a base.

[0289] The amount of use of the base is about 0.1-500 mol, preferablyabout 1-200 mol, per 1 mol of compound (bII).

[0290] Examples of the “base” include hydride of alkali metal oralkaline earth metal (e.g., lithium hydride, sodium hydride, potassiumhydride, calcium hydride etc.), amide of alkali metal or alkaline earthmetal (e.g., lithium amide, sodium amide, lithium diisopropylamide,lithium dicyclohexylamide, lithium hexamethyl disilazide, sodiumhexamethyl disilazide, potassium hexamethyl disilazide etc.), loweralkoxide of alkali metal or alkaline earth metal (e.g., sodiummethoxide, sodium ethoxide, potassium tert-butoxide etc.), carbonate ofalkali metal or alkaline earth metal (e.g., sodium carbonate, potassiumcarbonate etc.), hydrogencarbonate of alkali metal or alkaline earthmetal (e.g., sodium hydrogen carbonate, potassium hydrogen carbonateetc.), hydroxide of alkali metal or alkaline earth metal (e.g., sodiumhydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide),metal hydrocarbon (n-butyl lithium, tert-butyl lithium), organic bases[amines (e.g., triethylamine, diisopropylethylamine, N-methylmorpholine,dimethylaminopyridine, DBU (1,8-diazabicyclo[5.4.0]undec-7-ene), DBN(1,5-diazabicyclo[4.3.0]non-5-ene) etc.), organic base of basicheterocyclic compound (e.g., pyridine, imidazole, 2,6-lutidine etc.)etc.], and the like. Of these, hydrogencarbonate of alkali metal oralkaline earth metal is preferable. More preferred is sodium hydrogencarbonate.

[0291] The base may be used as it is or used after dissolving in aninert solvent. Examples of the “inert solvent” include theaforementioned “inert solvent”.

[0292] The temperature for treatment with a base is generally about0-70° C., preferably about 10-40° C. The reaction mixture may be leftstanding or stirred or immediately subjected to isolation andpurification of compound (bI) after addition of a base. When thereaction mixture is stood or stirred, the time of standing or stirringis generally about 0.01-5 hour, preferably about 0.1-2 hours.

[0293] The compound (bI) thus obtained can be isolated and purified froma reaction mixture by a known method, such as concentration,concentration under reduced pressure, solvent extraction,crystallization, recrystallization, phase transfer, chromatography andthe like.

[0294] Of the compounds (bI), for example, a compound of the formula

[0295] wherein R^(b1a), R^(b2a), R^(b7a) and R^(b8a) are each a hydrogenatom, R^(b9a) is phenyl having (i) optionally substituted hydroxy or(ii) optionally substituted thiol as substituent(s), and other symbolsare as defined above, and a salt thereof can be converted to a1-substituted-1,2,3-triazole compound useful as a pharmaceutical agentand the like, according to a method known per se, such as a methoddescribed in JP-A-11-60571 or a method analogous thereto.

[0296] The “optionally substituted hydroxy” of the “phenyl substitutedby optionally substituted hydroxy” represented by R^(b9a) is exemplifiedby those similar to the aforementioned “optionally substituted hydroxy”represented by R^(b4) or R^(b5) and the like.

[0297] The “optionally substituted thiol” of the “phenyl substituted byoptionally substituted thiol” represented by R^(b9a) is exemplified bythose similar to the aforementioned “optionally substituted thiol”represented by R^(b4), R^(b5), R^(b8) and the like.

[0298] For example, compound (bIa) is subjected to deprotection knownper se, where necessary, and reacted with a compound of the formula

R^(b16)-(CH₂)_(qb)-W^(b)

[0299] wherein R^(b16) is an optionally substituted aromaticheterocyclic group, qb is an integer of 1 to 5, and W^(b) is a leavinggroup, or a salt thereof [hereinafter to be briefly referred to ascompound (bIX)] to give a compound of the formula

[0300] wherein X^(b) is an oxygen atom or sulfur atom, and other symbolsare as defined above, or a salt thereof.

[0301] When the compound (bIX) is on the market, a commerciallyavailable product thereof may be used as it is, or compound (bIX) may beproduced according to a method known per se, a method analogous thereto,and the like.

[0302] Examples of the “leaving group” represented by W^(b) includehalogen (fluoro, chloro, bromo, iodo), alkylsulfonyloxy (e.g., C₁₋₆alkylsulfonyloxy such as methylsulfonyloxy etc.), arylsulfonyloxy (e.g.,C₆₋₁₄ arylsulfonyloxy optionally substituted by C₁₋₆ alkyl, such asp-toluenesulfonyloxy etc.) and the like.

[0303] The “aromatic heterocyclic group” of the “optionally substitutedaromatic heterocyclic group” represented by R^(b16) is exemplified by 5to 14-membered (preferably 5 to 10-membered) (monocyclic or bicyclic)heterocyclic group having, besides carbon atom, 1 or 2 kind(s) ofpreferably 1 to 4 hetero atom(s) selected from nitrogen atom, sulfuratom and oxygen atom and the like. Specific examples thereof include2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-oxazolyl, 4-oxazolyl,5-oxazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, 2-pyridyl, 3-pyridyl,4-pyridyl, 2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 8-quinolyl,1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, 2-pyrazinyl,2-pyrimidinyl, 4-pyrimidinyl, 3-pyrrolyl, 1-imidazolyl, 2-imidazolyl,4-imidazolyl, 5-imidazolyl, 3-pyridazinyl, 3-isothiazolyl,3-isooxazolyl, 1-indolyl, 2-indolyl, 3-indolyl, 2-benzothiazolyl,2-benzo[b]thienyl, 3-benzo[b]thienyl, 2-benzo[b]furanyl,3-benzo[b]furanyl and the like. Preferred is oxazolyl such as2-oxazolyl, 4-oxazolyl, 5-oxazolyl and the like.

[0304] The “substituent” of the “optionally substituted aromaticheterocyclic group” represented by R^(b16) is exemplified by 1 to 5 fromthe aforementioned “optionally substituted hydroxy”, “optionallysubstituted thiol”, “optionally substituted amino”, “optionallysubstituted hydrocarbon group”, “optionally substituted heterocyclicgroup”, “acyl” and the like represented by R^(b4) or R^(b5)″. Of these,optionally substituted hydrocarbon group is preferable, and C₂₋₆alkenylene substituted by optionally substituted C₆₋₁₄ aryl is morepreferable.

[0305] The amine compound such as compound (bII) can be also producedaccording to the method of the following Reaction b2.

[0306] (Reaction b2)

[0307] wherein each symbol is as defined above.

[0308] The compound (bIV) and compound (bV) are reacted to give compound(bVI), which is then subjected to reduction to give the objective aminecompound [compound (bVII)].

[0309] In the reaction of compound (bIV) and compound (bV), the amountof use of compound (bV) is about 0.1-10 mol, preferably about 1-2 mol,per 1 mol of compound (bIV).

[0310] The reaction of compound (bIV) and compound (bV) is carried outin the presence of an acid on demand.

[0311] Examples of the “acid” include Lewis acid (e.g., anhydrousaluminum chloride, zinc chloride, tin chloride etc.), and strong acid(e.g., sulfuric acid, methanesulfonic acid, trifluoromethanesulfonicacid etc.).

[0312] The amount of use of the “acid” is about 0.1-100 mol, preferablyabout 1-10 mol, per 1 mol of compound (bIV).

[0313] The reaction of compound (bIV) and compound (bV) is carried outwithout solvent or in a solvent inert to the reaction. Examples of the“inert solvent” include halogenated hydrocarbons (e.g., dichloromethane,chloroform, 1,2-dichloroethane, carbon tetrachloride etc.), aromatichydrocarbons (e.g., benzene, toluene, xylene, chlorobenzene etc.),ethers (e.g., diethyl ether, diisopropy ether, tert-butylmethyl ether,diphenyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyehtane etc.),aliphatic hydrocarbons (e.g., hexane, pentane, cyclohexane etc.), amides(e.g., N,N-dimethylformamide, N,N-dimethylacetamide,1-methyl-2-pyrrolidone, hexamethylphosphoric triamide etc.), sulfoxides(e.g., dimethyl sulfoxide etc.), nitrites (e.g., acetonitrile,propionitrile etc.) and a mixture of two or more of these. Preferably,the reaction is carried out without solvent.

[0314] The reaction temperature is generally from about −100° C. to 200°C., preferably from about 0° C. to 100° C. The reaction time isgenerally about 0.1 hour to 50 hours, preferably about 0.5 hour to 10hours.

[0315] The compound (bVI) thus obtained can be used in the next reactionas a reaction mixture or as a crude product. It is also possible toisolate the compound from the reaction mixture according to aconventional method and the compound can be easily purified by aseparation means such as recrystallization, distillation, chromatographyand the like.

[0316] Of the compounds (bVI), trifluoromethanesulfonic acid salt of thecompound of the formula

[0317] wherein R^(b12) is trimethylene and other symbols are as definedabove, is novel.

[0318] The compound (bVI) is reduced to give compound (bVII).

[0319] The reduction can be carried out according to catalytic reductionknown per se. The compound (bVI) and a catalytic amount of a metalcatalyst (e.g., Raney-nickel, platinum oxide, metal palladium,palladium-carbon etc.) are reacted in an inert solvent under hydrogenpressure of 0-100 atm, preferably 0-5 atm.

[0320] Examples of the “inert solvent” include halogenated hydrocarbons(e.g., dichloromethane, chloroform, 1,2-dichloroethane, carbontetrachloride etc.), aromatic hydrocarbons (e.g., benzene, toluene,xylene, chlorobenzene etc.), ethers (e.g., diethyl ether, diisopropyether, tert-butylmethyl ether, diphenyl ether, tetrahydrofuran, dioxane,1,2-dimethoxyethane etc.), aliphatic hydrocarbons (e.g., hexane,pentane, cyclohexane etc.), alcohols (e.g., methanol, ethanol,isopropylalcohol, 2-butanol, tert-butanol, 2-methyl-2-butanol etc.),amides (e.g., N,N-dimethylformamide, N,N-dimethylacetamide,1-methyl-2-pyrrolidone, hexamethylphosphoric triamide etc.), sulfoxides(e.g., dimethyl sulfoxide etc.), nitriles (e.g., acetonitrile,propionitrile etc.), organic acids (e.g., acetic acid etc.), water, amixture of two or more thereof and the like. Of these, ethers, aceticacid and the like are preferable.

[0321] The reaction temperature is from 0° C. to 100° C., preferablyfrom 20° C. to 70° C. The reaction time is generally about 0.5 hour to100 hours, preferably about 1 hour to 50 hours.

[0322] The compound (bVII) thus obtained can be used in the nextreaction as a reaction mixture or as a crude product. It is alsopossible to isolate the compound from the reaction mixture according toa conventional method and the compound can be easily purified by aseparation means such as recrystallization, distillation, chromatographyand the like.

[0323] The compound (bVII) can be converted to compound (bVIII) usefulas an intermediate for a 1-substituted-1,2,3-triazole compound having atyrosine kinase (especially, HER2) inhibitory action, by reacting thecompound with compound (bIII).

[0324] (Reaction b3)

[0325] wherein each symbol is as defined above.

[0326] The reaction of compound (bVII) and compound (bIII) can becarried out under the reaction conditions detailed in the aforementionedreaction b1.

[0327] The compound (bVIII) thus obtained can be isolated and purifiedfrom a reaction mixture by a known method, such as concentration,concentration under reduced pressure, solvent extraction,crystallization, recrystallization, phase transfer, chromatography andthe like.

[0328] Of the compounds (bVIII), for example, a compound of the formula

[0329] wherein R^(b12a) is C₁₋₁₀ alkylene and other symbols are asdefined above, or a salt thereof can be converted to a1-substituted-1,2,3-triazole compound useful as a pharmaceutical agentand the like, according to a method known per se, such as a methoddescribed in JP-A-11-60571 or a method analogous thereto.

[0330] For example, compound (bVIIIa) is subjected to deprotectionreaction known per se, and reacted with compound (bIX) to give acompound of the formula

[0331] wherein each symbol is as defined above, or a salt thereof.

[0332] The production method of compound (cIV) useful as an intermediatefor the production of an oxazole compound (cVII) having a tyrosinekinase (especially, HER2) inhibitory action is described in thefollowing.

[0333] (Reaction c1)

[0334] A reaction mixture of compound (cI) and compound (cII) is reactedwith compound (cIII) to give compound (cIV).

[0335] When the compound (cI) is on the market, a commercially availableproduct thereof may be used as it is, or compound (cI) may be producedaccording to a method known per se, a method analogous thereto, and thelike.

[0336] When the compound (cII) is on the market, a commerciallyavailable product thereof may be used as it is, or compound (cII) may beproduced according to a method known per se, a method analogous thereto,and the like.

[0337] When the compound (cIII) is on the market, a commerciallyavailable product thereof may be used as it is, or compound (cIII) maybe produced according to a method known per se, a method analogousthereto, and the like.

[0338] Preferably, the reaction of compound (cI) and compound (cII) iscarried out in the presence of an acid or a base and, where desired, ina solvent inert to the reaction.

[0339] The amount of use of compound (cII) is about 0.1-10 equivalents,preferably about 1-3 equivalents, relative to compound (cI).

[0340] The amount of use of acid is about 0.01-10 equivalents,preferably about 0.01-3 equivalents, relative to compound (cI).

[0341] The amount of use of base is about 0.01-10 equivalents,preferably about 0.01-3 equivalents, relative to compound (cI).

[0342] Examples of the “acid” include hydrochloric acid, sulfuric acid,trifluoromethanesulfonic acid, trifluoroacetic acid and the like.

[0343] Examples of the “base” include carbonate of alkali metal oralkaline earth metal (e.g., sodium carbonate, potassium carbonate etc.),hydrogencarbonate of alkali metal or alkaline earth metal (e.g., sodiumhydrogen carbonate, potassium hydrogen carbonate etc.), hydroxide ofalkali metal or alkaline earth metal (e.g., sodium hydroxide, potassiumhydroxide, lithium hydroxide, calcium hydroxide) and the like.

[0344] Examples of the “inert solvent” include aliphatic hydrocarbons(e.g., hexane, pentane, cyclohexane etc.), aromatic hydrocarbons (e.g.,benzene, toluene, xylene, chlorobenzene etc.), ethers (e.g., diethylether, diisopropy ether, tert-butylmethyl ether, diphenyl ether,tetrahydrofuran, dioxane, 1,2-dimethoxyethane etc.), halogenatedhydrocarbons (e.g., dichloromethane, chloroform, 1,2-dichloroethane,carbon tetrachloride etc.), esters (e.g., ethyl acetate etc.), ketones(e.g., acetone, methyl ethyl ketone etc.), nitriles (e.g., acetonitrile,propionitrile etc.), sulfoxides (e.g., dimethyl sulfoxide etc.), amides(e.g., N,N-dimethylformamide, N,N-dimethylacetamide,N-methylpyrrolidone, hexamethylphosphoric triamide etc.), alcohols(e.g., methanol, ethanol, isopropyl alcohol, 2-butanol, tert-butanol,2-methyl-2-butanol etc.), water, a mixture of two or more thereof andthe like. Of these, aromatic hydrocarbons such as toluene, xylene andthe like are preferable.

[0345] The reaction temperature is generally from about 0° C. to 200°C., preferably from about 20° C. to 160° C. The reaction time isgenerally about 1 hour to 48 hours, preferably about 1 hour to 24 hours.

[0346] The reaction of compound (cIII) and a reaction mixture ofcompound (cI) and compound (cII) is preferably carried out in thepresence of a base and(or) a phase transfer catalyst and in a solventinert to the reaction, where desired.

[0347] The compound (cIII) may be an anhydride or hydrate.

[0348] The amount of use of compound (cIII) is about 0.1-10 equivalents,preferably about 1-8 equivalents, relative to compound (cI).

[0349] The amount of use of base is about 0.1-10 equivalents, preferablyabout 1-8 equivalents, relative to compound (cI).

[0350] The amount of use of the phase transfer catalyst is about 0.01-1equivalent, preferably about 0.01-0.3 equivalent, relative to compound(cI).

[0351] Examples of the “base” include carbonate of alkali metal oralkaline earth metal (e.g., sodium carbonate, potassium carbonate etc.),hydrogencarbonate of alkali metal or alkaline earth metal (e.g., sodiumhydrogen carbonate, potassium hydrogen carbonate etc.), hydroxide ofalkali metal or alkaline earth metal (e.g., sodium hydroxide, potassiumhydroxide, lithium hydroxide, calcium hydroxide) and the like.

[0352] Examples of the “phase transfer catalyst” includetetra(n-butyl)ammonium bromide, tetra(n-butyl)ammonium hydrogensulfateand the like.

[0353] Examples of the “inert solvent” include aliphatic hydrocarbons(e.g., hexane, pentane, cyclohexane etc.), aromatic hydrocarbons (e.g.,benzene, toluene, xylene, chlorobenzene etc.), ethers (e.g., diethylether, diisopropy ether, tert-butylmethyl ether, diphenyl ether,tetrahydrofuran, dioxane, 1,2-dimethoxyethane etc.), halogenatedhydrocarbons (e.g., dichloromethane, chloroform, 1,2-dichloroethane,carbon tetrachloride etc.), esters (e.g., ethyl acetate etc.), ketones(e.g., acetone, methyl ethyl ketone etc.), nitrites (e.g., acetonitrile,propionitrile etc.), sulfoxides (e.g., dimethyl sulfoxide etc.), amides(e.g., N,N-dimethylformamide, N,N-dimethylacetamide,N-methylpyrrolidone, hexamethylphosphoric triamide etc.), alcohols(e.g., methanol, ethanol, isopropyl alcohol, 2-butanol, tert-butanol,2-methyl-2-butanol etc.), water, a mixture of two or more thereof andthe like. Of these, dimethyl sulfoxide, N,N-dimethylformamide,N-methylpyrrolidone and the like are preferable.

[0354] The reaction temperature is generally from about 0° C. to 150°C., preferably from about 20° C. to 130° C. The reaction time isenerally about 1 hour to 24 hours, preferably about 1 hour to 12 hours.

[0355] The compound (cIV) thus obtained can be isolated and purifiedfrom a reaction mixture by a known method, such as concentration,concentration under reduced pressure, solvent extraction,crystallization, recrystallization, phase transfer, chromatography andthe like.

[0356] In the above-mentioned reaction, the reaction product fromcompound (cI) and compound (cII) can be isolated from the reactionmixture according to a conventional method, but preferably, the reactionproduct is subjected to the next step without isolation.

[0357] The compound (cIV) can be converted to compound (cVII) useful asa pharmaceutical agent and the like, for example, according to thefollowing Reactions c2 and c3.

[0358] (Reaction c2)

[0359] The compound (cIV) is subjected to hydrolysis or catalyticreduction to give compound (cV).

[0360] For “hydrolysis”, compound (cIV) and a base are reacted in aninert solvent.

[0361] The amount of use of base is about 0.1-10 equivalents, preferably1-5 equivalents, relative to compound (cIV).

[0362] Examples of the “base” include carbonate of alkali metal oralkaline earth metal (e.g., sodium carbonate, potassium carbonate etc.),hydroxide of alkali metal or alkaline earth metal (e.g., sodiumhydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide)and the like.

[0363] Examples of the “inert solvent” include aliphatic hydrocarbons(e.g., hexane, pentane, cyclohexane etc.), aromatic hydrocarbons (e.g.,benzene, toluene, xylene, chlorobenzene etc.), ethers (e.g., diethylether, diisopropy ether, tert-butylmethyl ether, diphenyl ether,tetrahydrofuran, dioxane, 1,2-dimethoxyethane etc.), halogenatedhydrocarbons (e.g., dichloromethane, chloroform, 1,2-dichloroethane,carbon tetrachloride etc.), esters (e.g., ethyl acetate etc.), ketones(e.g., acetone, methyl ethyl ketone etc.), nitriles (e.g., acetonitrile,propionitrile etc.), sulfoxides (e.g., dimethyl sulfoxide etc.), amides(e.g., N,N-dimethylformamide, N,N-dimethylacetamide,N-methylpyrrolidone, hexamethylphosphoric triamide etc.), alcohols(e.g., methanol, ethanol, isopropyl alcohol, 2-butanol, tert-butanol,2-methyl-2-butanol etc.), water, a mixture of two or more thereof andthe like. Preferred are methanol and dimethyl sulfoxide.

[0364] The reaction temperature is generally from about 0° C. to 150°C., preferably from about 20° C. to 130° C. The reaction time isgenerally about 1 hour to 24 hours, preferably about 1 hour to 12 hours.

[0365] For “hydrolysis”, compound (cIV) and an acid are reacted in aninert solvent.

[0366] The amount of use of acid is about 0.1-10 equivalents, preferably1-5 equivalents, relative to compound (cIV).

[0367] Examples of the “acid” include mineral acid such as hydrochloricacid, hydrobromic acid etc., and the like.

[0368] As the “inert solvent”, for example, water and organic acid(e.g., acetic acid etc.) and the like can be mixed for use.

[0369] The reaction temperature is generally from about 0° C. to 150°C., preferably from about 20° C. to 130° C. The reaction time isgenerally about 1 hour to 48 hours, preferably about 1 hour to 24 hours.

[0370] For “catalytic reduction”, compound (cIV) and a catalytic amountof a metal catalyst (e.g., Raney-nickel, platinum oxide, metalpalladium, palladium-carbon etc., preferably, palladium-carbon) arereacted in an inert solvent under a hydrogen pressure of 1-100 atm at0-100° C. for about 1-48 hours. Preferable reaction conditions are 1-10atm hydrogen pressure, at about 20-100° C. for about 1-24 hours.

[0371] Where necessary, an acid (e.g., hydrochloric acid, phosphoricacid, perchloric acid, sulfuric acid) and the like may be added in acatalytic amount (equivalent or in excess).

[0372] Examples of the “inert solvent” include organic acids (e.g.,acetic acid, propionic acid), alcohols (e.g., methanol, ethanol,isopropylalcohol, 2-butanol, tert-butanol, 2-methyl-2-butanol etc.),ethers (e.g., diethyl ether, diisopropy ether, tert-butylmethyl ether,diphenyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane etc.),aliphatic hydrocarbons (e.g., hexane, pentane, cyclohexane etc.),aromatic hydrocarbons (e.g., benzene, toluene, xylene, chlorobenzeneetc.), water, a mixture of two or more thereof and the like.

[0373] The compound (cV) thus obtained can be isolated and purified froma reaction mixture by a known method, such as concentration,concentration under reduced pressure, solvent extraction,crystallization, recrystallization, phase transfer, chromatography andthe like.

[0374] (Reaction c3)

[0375] The compound (cV) is subjected to sulfonylation or halogenationreaction and then reacted with compound (cVI) to give compound (cVII).Specifically, compound (cV) and a sulfonylating agent or halogenatingagent are reacted in an inert solvent in the presence of a base, wheredesired.

[0376] When the compound (cIV) is on the market, a commerciallyavailable product thereof may be used as it is, or compound (cIV) may beproduced according to a method known per se, a method analogous thereto,and the like.

[0377] The amount of use of sulfonylating agent is about 0.1-10equivalents, preferably 1-3 equivalents, relative to compound (cV).

[0378] The amount of use of halogenating agent is about 0.1-10equivalents, preferably 1-3 equivalents, relative to compound (cV).

[0379] The amount of use of base is about 0.1-10 equivalents, preferably1-3 equivalents, relative to compound (cV).

[0380] Examples of the “sulfonylating agent” include R⁵—SO₂Cl such asmethanesulfonyl chloride, p-toluenesulfonyl chloride etc., and the like.

[0381] Examples of the “halogenating agent” include thionyl chloride,oxalyl chloride and the like.

[0382] Examples of the “base” include carbonate of alkali metal oralkaline earth metal (e.g., sodium carbonate, potassium carbonate etc.),hydroxide of alkali metal or alkaline earth metal (e.g., sodiumhydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide),organic base (e.g., diisopropylethylamine, triethylamine, pyridine etc.)and the like.

[0383] Examples of the “inert solvent” include aliphatic hydrocarbons(e.g., hexane, pentane, cyclohexane etc.), aromatic hydrocarbons (e.g.,benzene, toluene, xylene, chlorobenzene etc.), ethers (e.g., diethylether, diisopropy ether, tert-butylmethyl ether, diphenyl ether,tetrahydrofuran, dioxane, 1,2-dimethoxyethane etc.), halogenatedhydrocarbons (e.g., dichloromethane, chloroform, 1,2-dichloroethane,carbon tetrachloride etc.), esters (e.g., ethyl acetate etc.), ketones(e.g., acetone, methyl ethyl ketone etc.), nitriles (e.g., acetonitrile,propionitrile etc.), sulfoxides (e.g., dimethyl sulfoxide etc.), amides(e.g., N,N-dimethylformamide, N,N-dimethylacetamide,N-methylpyrrolidone, hexamethylphosphoric triamide etc.), alcohols(e.g., methanol, ethanol, isopropyl alcohol, 2-butanol, tert-butanol,2-methyl-2-butanol etc.) and a mixture of two or more of these.Preferred are tetrahydrofuran, acetonitrile, acetone and the like.

[0384] The reaction temperature is generally from about −40° C. to 100°C., preferably from about −20° C. to 80° C. The reaction time isgenerally about 1 hour to 12 hours, preferably about 1 hour to 6 hours.

[0385] Then, the thus-obtained reaction mixture and compound (cVI) arereacted in an inert solvent in the presence of a base and(or) a phasetransfer catalyst, where desired, to give compound (cVII).

[0386] When the compound (cIV) is on the market, a commerciallyavailable product thereof may be used as it is, or compound (cIV) may beproduced according to a method known per se, a method analogous thereto,and the like.

[0387] The amount of use of compound (cVI) is about 0.1-10 equivalents,preferably about 1-3 equivalents, relative to compound (cV).

[0388] The amount of use of base is about 1-100 equivalents, preferablyabout 1-10 equivalents, relative to compound (cV).

[0389] The amount of use of the phase transfer catalyst is about 0.01-1equivalent, preferably about 0.01-0.3 equivalent, relative to compound(cV).

[0390] Examples of the “base” include carbonate of alkali metal oralkaline earth metal (e.g., sodium carbonate, potassium carbonate etc.),hydroxide of alkali metal or alkaline earth metal (e.g., sodiumhydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide)and the like.

[0391] Examples of the “phase transfer catalyst” includetetra(n-butyl)ammonium bromide, tetra(n-butyl)ammonium hydrogensulfateand the like.

[0392] Examples of the “inert solvent” include aliphatic hydrocarbons(e.g., hexane, pentane, cyclohexane etc.), aromatic hydrocarbons (e.g.,benzene, toluene, xylene, chlorobenzene etc.), ethers (e.g., diethylether, diisopropy ether, tert-butylmethyl ether, diphenyl ether,tetrahydrofuran, dioxane, 1,2-dimethoxyethane etc.), halogenatedhydrocarbons (e.g., dichloromethane, chloroform, 1,2-dichloroethane,carbon tetrachloride etc.), esters (e.g., ethyl acetate etc.), ketones(e.g., acetone, methyl ethyl ketone etc.), nitrites (e.g., acetonitrile,propionitrile etc.), sulfoxides (e.g., dimethyl sulfoxide etc.), amides(e.g., N,N-dimethylformamide, N,N-dimethylacetamide,N-methylpyrrolidone, hexamethylphosphoric triamide etc.), alcohols(e.g., methanol, ethanol, isopropyl alcohol, 2-butanol, tert-butanol,2-methyl-2-butanol etc.), water, a mixture of two or more thereof andthe like. Preferred are tetrahydrofuran, acetonitrile, acetone, waterand the like.

[0393] The reaction temperature is generally from about 0° C. to 150°C., preferably from about 20° C. to 130° C. The reaction time isgenerally about 1 hour to 24 hours, preferably about 1 hour to 12 hours.

[0394] The compound (cVII) thus obtained can be isolated and purifiedfrom a reaction mixture by a known method, such as concentration,concentration under reduced pressure, solvent extraction,crystallization, recrystallization, phase transfer, chromatography andthe like.

[0395] The compound (cVII) useful as a pharmaceutical agent and the likecan be also produced according to the following Reactions c4-c5.

[0396] (Reaction c4)

[0397] A reaction mixture of compound (cI) and compound (cII) is reactedwith compound (cIII), and then the obtained compound is subjected tohydrolysis to give compound (cV).

[0398] The conditions for “a reaction mixture of compound (cI) andcompound (cII) is reacted with compound (cIII)” are the same as inReaction c1.

[0399] The “hydrolysis” only needs to follow the reaction described inReaction c2, and the amount of use of base is about 0.1-10 equivalents,preferably 1-5 equivalents, relative to compound (cI). The amount of useof acid is about 0.1-10 equivalents, preferably 1-5 equivalents,relative to compound (cI).

[0400] (Reaction c5)

[0401] The compound (cV) obtained in Reaction c4 is subjected tosulfonylation or halogenation and then reacted with compound (cVI) togive compound (cVII).

[0402] The reaction conditions are the same as in Reaction c3.

[0403] The compound (cVIIa) useful as a pharmaceutical agent and thelike can be also produced according to the following Reaction c6 orReaction c7.

[0404] (Reaction c6)

[0405] A reaction mixture of compound (cIa) and compound (cII) issubjected to hydrolysis and the obtained compound (cVa) is subjected tosulfonylation or halogenation and then reacted with compound (cVI) togive compound (cVIIa).

[0406] This reaction only needs to follow the above-mentioned Reactionsc1-c3. As a usable “base”, for example, carbonate of alkali metal oralkaline earth metal (e.g., sodium carbonate, potassium carbonate etc.)and the like are preferable.

[0407] (Reaction c7)

[0408] A reaction mixture of compound (cIa) and compound (cII) isreacted with compound (cVI) to give compound (cVIIa).

[0409] This reaction only needs to follow the above-mentioned Reactionsc1-c3.

[0410] The compounds (aVa), (aVb), (bX), (bXI) and (cVII) [inclusive ofcompound (cVIIa)] are useful as pharmaceutical agents, agriculturalchemicals and the like.

[0411] The compounds (aVa), (aVb), (bX), (bXI) and (cVII) have atyrosine kinase inhibitory action and can be used for the prophylaxis ortreatment of tyrosine kinase-dependent diseases in mammal. The tyrosinekinase-dependent diseases include diseases caused by enhanced cellproliferation due to abnormal tyrosine kinase enzyme activity.Furthermore, since compounds (aVa), (aVb), (bX), (bXI) and (cVII)specifically inhibit HER2 tyrosine kinase, they are useful as atherapeutic agent for inhibiting growth of cancer that expresses HER2,or as an agent for preventing metastasis of hormone dependent cancer tohormone non-dependent cancer. That is, compounds (aVa), (aVb), (bX),(bXI) and (cVII) can be used as safe agents for the prophylaxis ortreatment of diseases caused by abnormal cell growth such as variouscancers (particularly breast cancer, prostate cancer, pancreatic cancer,stomach cancer), atherosclerosis, angiogenesis (e.g., angiogenesisaccompanying growth of solid tumor and sarcoma, angiogenesis associatedwith tumor metastasis, angiogenesis associated with diabetic retinopathyetc.), viral diseases (HIV infection etc.) and the like. The tyrosinekinase-dependent diseases further include abnormal tyrosine kinaseenzyme activity-related cardiovascular diseases. Therefore, thecompounds (aVa), (aVb), (bX), (bXI) and (cVII) can be also used as anagent for the prophylaxis or treatment of cardiovascular diseases suchas restenosis.

[0412] The compounds (aVa), (aVb), (bX), (bXI) and (cVII) have atyrosine kinase inhibitory action and can be used for the prophylaxis ortreatment of tyrosine kinase-dependent diseases in mammal. The tyrosinekinase-dependent diseases include diseases caused by enhanced cellproliferation due to abnormal tyrosine kinase enzyme activity.Furthermore, since compounds (aVa), (aVb), (bX), (bXI) and (cVII)specifically inhibit HER2 tyrosine kinase, they are useful as atherapeutic agent for inhibiting growth of cancer that expresses HER2,or as an agent for preventing metastasis of hormone dependent cancer tohormone non-dependent cancer.

[0413] That is, compounds (aVa), (aVb), (bX), (bXI) and (cVII) can beused as safe agents for the prophylaxis or treatment of diseases causedby abnormal cell growth such as various cancers (particularly breastcancer, prostate cancer, pancreatic cancer, stomach cancer, lung cancer,colon cancer, rectal cancer, esophageal cancer, duodenal carcinoma,tongue cancer, pharyngeal cancer, brain tumor, neurinomatosis, non-smallcell lung cancer, small cell lung carcinoma, liver cancer, kidneycancer, bile duct cancer, cancer of uterine body, cervical carcinoma,ovarian cancer, bladder cancer, skin cancer, angiomatosis, malignantlymphoma, malignant melanoma, thyroid cancer, bone tumor, angiofibroma,retinal sarcoma, penile cancer, childhood solid cancer, Kaposi'ssarcoma, AIDS related Kaposi's sarcoma, cancer of maxillary sinus,fibrous histiocytoma, leiomyosarcoma, rhabdomyosarcoma, leukemia etc.),atherosclerosis, angiogenesis (e.g., angiogenesis accompanying growth ofsolid tumor and sarcoma, angiogenesis associated with tumor metastasis,angiogenesis associated with diabetic retinopathy etc.), viral diseases(HIV infection and the like.

[0414] The tyrosine kinase-dependent diseases further include abnormaltyrosine kinase enzyme activity-related cardiovascular diseases.Therefore, the compounds (aVa), (aVb), (bX), (bXI) and (cVII) can bealso used as an agent for the prophylaxis or treatment of cardiovasculardiseases such as restenosis.

[0415] The compounds (aVa), (aVb), (bX), (bXI) and (cVII) are useful asanticancer agents for the prophylaxis or treatment of cancer,particularly breast cancer, prostate cancer, pancreatic cancer, stomachcancer, lung cancer, colon cancer and large bowel cancer.

[0416] The compounds (aVa), (aVb), (bX), (bXI) and (cVII) show lowtoxicity and can be used as they are as pharmaceutical agents or as apharmaceutical composition in admixture with a pharmacologicallyacceptable carrier known per se for mammal such as human, horse, cattle,dog, cat, rat, mouse, rabbit, pig, monkey and the like.

[0417] A pharmaceutical composition may contain, along with the compound(aVa), (aVb), (bX), (bXI) or (cVII), other active ingredient, such ashormone preparation, anticancer agents (e.g., chemotherapy agent,immunotherapy agent and pharmaceutical agent inhibiting the action ofcell growth factor and receptor thereof etc.) and the like.

[0418] When the compound (aVa), (aVb), (bX), (bXI) or (cVII) isadministered as a pharmaceutical agent to mammal such as human, theadministration route is oral administration in the form of, for example,tablets, capsules (inclusive of soft capsule and microcapsule), powders,granules and the like, or parenteral administration in the form ofinjection, suppository, pellet and the like. By the “parenterally” ismeant intravenous, intramuscular, subcutaneous, intraorgan, intranasal,intradermal, instillation, intracerebral, intrarectal, intravaginal andintraperitoneal administrations, administration into tumor,administration to the vicinity of tumor and direct administration to thefocus. While the dose of the compound (aVa), (aVb), (bX), (bXI) or(cVII) varies depending on the administration route, symptoms and thelike, when, for example, it is orally administered as an anticanceragent to a patient weighing 40 to 80 kg having, for example, breastcancer or prostate cancer, it is 0.5-100 mg/kg body weight, preferably1-50 mg/kg body weight, more preferably 1-25 mg/kg body weight, which isadministered once a day or in 2 or 3 doses a day.

[0419] The compound (aVa), (aVb), (bX), (bXI) or (cVII) is admixed witha pharmacologically acceptable carrier and administered orally orparenterally as a solid preparation such as tablet, capsule, granule,powder and the like or a liquid preparation such as syrup, injection andthe like.

[0420] As the pharmacologically acceptable carrier usable for theproduction of the pharmaceutical composition, there are mentionedvarious conventional organic or inorganic carriers as a material for thepreparation. Examples thereof include excipients, lubricants, bindersand disintegrators for solid preparations, and solvents, solubilizingaids, suspending agents, isotonic agents, buffers and soothing agentsfor liquid preparations. Where necessary, conventional additives such asantiseptics, antioxidants, coloring agents, sweeteners and the like canbe used.

[0421] As preferable examples of the excipient, there are mentioned, forexample, lactose, sucrose, D-mannitol, starch, crystalline cellulose,light anhydrous silicic acid and the like.

[0422] As preferable examples of the lubricant, there are mentioned, forexample, magnesium stearate, calcium stearate, talc, colloidal silicaand the like.

[0423] As preferable examples of the binder, there are mentioned, forexample, crystalline cellulose, sucrose, D-mannitol, dextrin,hydroxypropylcellulose, hydroxypropylmethylcellulose,polyvinylpyrrolidone and the like.

[0424] As preferable examples of the disintegrator, there are mentioned,for example, starch, carboxymethylcellulose, carboxymethylcellulosecalcium, crosscarmellose, sodium carboxymethyl starch and the like.

[0425] As preferable examples of the solvent, there are mentioned, forexample, injectable water, alcohol, propylene glycol, Macrogol, sesameoil, corn oil and the like.

[0426] As preferable examples of the solubilizing aid, there arementioned, for example, polyethylene glycol, propylene glycol,D-mannitol, benzyl benzoate, ethanol, tris-aminomethane, cholesterol,triethanolamine, sodium carbonate, sodium citrate and the like.

[0427] As preferable examples of the suspending agent, there arementioned, for example, surfactants such as stearyl triethanolamine,sodium lauryl sulfate, lauryl aminopropionic acid, lecithin,benzalkonium chloride, benzethonium chloride, glyceryl monostearate andthe like; hydrophilic polymers such as polyvinyl alcohol,polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose,hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcelluloseand the like.

[0428] As preferable examples of the isotonicity agent, there arementioned, for example, sodium chloride, glycerine, D-mannitol and thelike.

[0429] As preferable examples of the buffer, there are mentioned, forexample, buffers such as phosphate, acetate, carbonate, citrate and thelike.

[0430] As preferable examples of the soothing agent, there arementioned, for example, benzyl alcohol and the like.

[0431] As preferable examples of the antiseptic, there are mentioned,for example, p-oxybenzoates, chlorobutanol, benzyl alcohol, phenethylalcohol, dehydroacetic acid, sorbic acid and the like.

[0432] As preferable examples of the antioxidant, there are mentioned,for example, sulfite, ascorbic acid and the like.

[0433] While the pharmaceutical composition varies depending on thedosage form, administration method, carrier and the like, it can beproduced according to a conventional method by adding compound (aVa),(aVb), (bX), (bXI) or (cVII) generally in an amount of 0.1-95%(w/w) ofthe entire amount of the preparation.

[0434] In addition, by (1) administering an effective amount of compound(aVa), (aVb), (bX), (bXI) or (cVII), (2) (i) administering an effectiveamount of a different anticancer agent, (ii) administering an effectiveamount of a hormone preparation, or (iii) by combining 1 to 3 kinds froma group consisting of therapies without medicine, cancer can be moreeffectively prevented or treated. As the therapy without medicine, thereare mentioned, for example, operation, radiation therapy, gene therapy,thermotherapy, cryotherapy, laser cauterization therapy and the like,and two or more of these can be combined.

[0435] For example, the compound of the present invention can be used incombination with other hormone preparations, anticancer agents (e.g.,chemotherapy agent, immunotherapy agent and pharmaceutical agentinhibiting the action of cell growth factor and receptor thereof) andthe like (hereinafter to be briefly referred to as combination drug).

[0436] While the compounds (aVa), (aVb), (bX), (bXI) or (cVII) shows asuperior anticancer effect even when used as a single agent, when it isused in combination with one or more of the above-mentioned combinationdrugs (combined use of plural agents), the effect can be reinforcedfurthermore.

[0437] Examples of the “hormone preparation” include fosfestrol,diethylstilbestrol, chlorotrianiseline, medroxyprogesterone acetate,megesterol acetate, chlormadinone acetate, cyproterone acetate, danazol,allylestrenol, gestrinone, mepartricine, raloxifene, ormeloxifene,levormeloxifene, antiestrogen (e.g., tamoxifen citrate, toremifenecitrate etc.), contraceptive pill, mepitiostane, testolactone,aminoglutethimide, LH-RH agonist (e.g., goserelin acetate, buserelin,leuprorelin etc.), droloxifene, epitiostanol, ethinylestradiolsulfonate, aromatase inhibitor (e.g., fadrozole hydrochloride,anastrozole, letrozole, exemestane, vorozole, formestane etc.),antiandrogen (e.g., flutamide, bicalutamide, nilutamide etc.),5α-reductase inhibitor (e.g., finasteride, epristeride etc.),adrenocortical hormone preparation (e.g., dexamethasone, prednisolone,betamethasone, triamcinolone etc.), androgen synthesis inhibitor (e.g.,abiraterone etc. and lyase inhibitor), retinoid and an agent to delaymetabolism of retinoid (e.g., liarozole etc.) and the like. Of these,LH-RH agonist (e.g., goserelin acetate, buserelin, leuprorelin etc.) ispreferable.

[0438] Examples of the “chemotherapy agent” include alkylating agent,antimetabolite, carcinostatic antibiotics, plant alkaloid and the like.

[0439] Examples of the “alkylating agent” include nitrogen mustard,nitrogen mustard-n-oxide hydrochloride, chrorambucil, cyclophosphamide,ifosfamide, thiotepa, carboquone, improsulfan tosilate, busulfan,nimustine hydrochloride, mitobronitol, melphalan, dacarbazine,ranimustine, sodium estramustine phosphate, triethylene melamine,carmustine, lomustine, streptozocin, pipobroman, etoglucide, altretamin,ambamustine, dibrospidium hydrochloride, fotemustine, prednimustine,pumitepa, ribomustin, temozolomide, treosulfan, trophosphamide,zinostatin stimalamer, carboquone, adozelesin, cystemstin, bizelesin,platinym complex (carboplatin, cisplatin, miboplatin, nedaplatin,oxaliplatin etc.) and the like.

[0440] Examples of the “antimetabolite” include mercaptopurine,6-mercaptopurine riboside, thioinosine, methotrexate, enocitabine,cytarabine, cytarabine ocphosphate, ancitabine hydrochloride, 5-FUpharmaceutical agents (e.g., fluorouracil, tegafur, UFT, doxifluridine,carmofur, galocitabine, emitefur etc.), aminopterin, calcium leucovorin,tabloid, butocin, calcium folinate, calcium levofolinate, cladribine,emitefur, fludarabine, gemcitabine, hydroxycarbamide, pentostatin,piritrexim, idoxuridine, mitoguazone, tiazofurin, ambamstine and thelike.

[0441] Examples of the “carcinostatic antibiotics” include anthracyclincarcinostatic agents (doxorubicin hydrochloride, daunorubicinhydrochloride, aclarubicin hydrochloride, pirarubicin hydrochloride,epirubicin hydrochloride etc.), actinomycin D, actinomycin C, mitomycinC, chromomycin A3, bleomycin hydrochloride, bleomycin sulfate,peplomycin sulfate, neocarzinostatin, mithramycin, sarcomycin,carzinophilin, mitotane, zorubicin hydrochloride, mitoxantronehydrochloride, idarubicin hydrochloride and the like.

[0442] Examples of the “plant alkaloid” include vinca alkaloidcarcinostatic agents (vinblastine sulfate, vincristine sulfate,vindesine sulfate etc.), taxan anticancer agents (paclitaxel, docetaxeletc.), etoposide, etoposide phosphate, teniposide, vinorelbine and thelike.

[0443] Examples of the “immunotherapeutic agent” (BRM) includepicibanil, krestin, sizofiran, lentinan, ubenimex, interferon,interleukin, macrophage colony stimulating factor, granulocyte-colonystimulating factor, erythropoietin, lymphotoxin, BCG vaccine,Corynebacterium parvum, levamisole, polysaccharide K, procodazol and thelike.

[0444] As the “cell growth factor” in the “pharmaceutical agentinhibiting action of the cell growth factor and its receptor”, anysubstance can be used as long as it enhances proliferation of cells. Ingeneral, a factor which is a peptide having a molecular weight of notmore than 20,000, and which can show effect upon binding with receptorat a low concentration is exemplified. Specific examples include (1) EGF(epidermal growth factor) or a substance having substantially the sameactivity therewith [e.g., EGF, heregulin (HER2 ligand) etc.], (2)insulin or a substance having substantially the same activity therewith[e.g., insulin, IGF (insulin-like growth factor)-1, IGF-2 etc.], (3) FGF(fibroblast growth factor) or a substance having substantially the sameactivity therewith [e.g., acidic FGF, basic FGF, KGF (keratinocytegrowth factor), FGF-10 etc.], (4) other cell growth factors [e.g., CSF(colony stimulating factor), EPO (erythropoietin), IL-2(interleukin-2),NGF (nerve growth factor), PDGF (platelet-derived growth factor), TGFβ(transforming growth factor β), HGF (hepatocyte growth factor), VEGF(vascular endothelial growth factor) etc.] and the like.

[0445] The “receptor of the cell growth factor” may be any receptor aslong as it has a binding ability with the above-mentioned cell growthfactor. Specific examples include EGF receptor, heregulin receptor(HER2), insulin receptor, IGF receptor, FGF receptor-1, FGF receptor-2,HGF receptor (c-met), VEGF receptor, SCF receptor (c-kit), and the like.

[0446] Examples of the “pharmaceutical agent inhibiting action of thecell growth factor” include herceptin (HER2 antibody), GLEEVEC (c-met,c-kit, abl inhibitor), Iressa (EGF receptor inhibitor) and the like.

[0447] In addition to the aforementioned pharmaceutical agents,L-asparaginase, aceglatone, procarbazine hydrochloride, cobaltprotoporphyrin.complex, mercurial hematoporphyrin.sodium, topoisomeraseI inhibitor (e.g., irinotecan, topotecan etc.), topoisomerase IIinhibitor (e.g., sobuzoxane etc.), differentiation inducing agent (e.g.,retinoid, vitamine D etc.), angiogenesis inhibitor, α-blocker (e.g.,tamsulosin hydrochloride etc.) and the like can be also used.

[0448] Of the above-mentioned combination drugs, LH-RH agonist (e.g.,goserelin acetate, buserelin acetate, leuprorelin acetate etc.),herceptin (HER2 antibody) and the like are preferable.

[0449] For the combined use of compound (aVa), (aVb), (bX), (bXI) or(cVII) and combination drug, the time of administration of compound(aVa), (aVb), (bX), (bXI) or (cVII) and combination drug is not limited.The compound (aVa), (aVb), (bX), (bXI) or (cVII) and combination drugmay be simultaneously administered to an administration object oradministered in a staggered manner. The dose of the combination drugonly needs to follow the dose clinically employed, and can be determinedas appropriate depending on the administration object, administrationroute, disease, combination and the like.

[0450] The mode of administration of the compound (aVa), (aVb), (bX),(bXI) or (cVII) and combination drug(s) is not particularly limited, andmay be any as long as the compound (aVa), (aVb), (bX), (bXI) or (cVII)and combination drug(s) are combined on administration. Suchadministration mode is exemplified by (1) administration of a singlepreparation obtained by simultaneously formulating the compound (aVa),(aVb), (bX), (bXI) or (cVII) and combination drug(s) into a preparation,(2) simultaneous administration by the same administration route of twokinds of preparations obtained by separately formulating the compound(aVa), (aVb), (bX), (bXI) or (cVII) and combination drug(s) intopreparations, (3) staggered administration by the same administrationroute of two kinds of preparations obtained by separately formulatingthe compound (aVa), (aVb), (bX), (bXI) or (cVII) and combination drug(s)into preparations, (4) simultaneous administration by differentadministration routes of two kinds of preparations obtained byseparately formulating the compound (aVa), (aVb), (bX), (bXI) or (cVII)and combination drug(s) into preparations, (5) staggered administrationby different administration routes of two kinds of preparations obtainedby separately formulating the compound (aVa), (aVb), (bX), (bXI) or(cVII) and combination drug(s) into preparations (e.g., administrationin the order of compound (aVa), (aVb), (bX), (bXI) or (cVII)→combinationdrug, and administration in the reversed order) and the like. Thesemodes of administrations are collectively referred to in the followingas a combination agent of the present invention.

[0451] The combination agent of the present invention has low toxicityand can be administered safely by admixing the compound (aVa), (aVb),(bX), (bXI) or (cVII) and/or combination drug(s) with, for example, apharmacologically acceptable carrier according to a method known per seto give a pharmaceutical composition, such as tablets (inclusive ofsugar-coated tablets and film-coated tablets), powders, granules,capsules, (inclusive of soft capsules), liquids, injections,suppositories, sustained release agents and the like, for oral orparenteral (e.g., topical, rectal or intravenous administration)administration. An injection can be administered intravenously,intramuscularly, subcutaneously, into the organ, intranasally,intradermally, by instillation, intracerebrally, intrarectally,intravaginally, intraperitoneally, into tumor, to the vicinity of tumoror directly to the focus.

[0452] As the pharmacologically acceptable carrier usable for theproduction of the combination agent of the present invention, there arementioned those usable for the aforementioned pharmaceuticalcomposition.

[0453] The content ratio of the compound (aVa), (aVb), (bX), (bXI) or(cVII) and combination drug in the combination agent of the presentinvention can be appropriately determined depending on theadministration object, administration route, disease and the like.

[0454] For example, the content of the compound (aVa), (aVb), (bX),(bXI) or (cVII) in the combination agent of the present invention isgenerally about 0.01-100 wt %, preferably about 0.1-50 wt %, morepreferably about 0.5-20 wt %, based on the preparation in total, thoughthey may change depending on the preparation form.

[0455] The content of the combination drug in the combination agent ofthe present invention is generally about 0.01-100 wt %, preferably about0.1-50 wt %, more preferably about 0.5-20 wt %, based on the preparationin total, though may change depending on the preparation form.

[0456] The content of the additive in the combination agent of thepresent invention varies depending on the form of the preparation. It isgenerally about 1-99.99 wt %, preferably about 10-90 wt %, based on thepreparation in total.

[0457] The same contents are employed when the compound (aVa), (aVb),(bX), (bXI) or (cVII) and combination drug(s) are formulated separatelyinto preparations.

[0458] These preparations can be produced by a method known per se,which is generally employed for the preparation steps.

[0459] For example, the compound (aVa), (aVb), (bX), (bXI) or (cVII), ora combination drug can be prepared into an aqueous injection togetherwith a dispersant (e.g., Tween 80 (ATLASPOWDER USA), HCO60 (NIKKOCHEMICALS), polyethylene glycol, carboxymethylcellulose, sodiumarginate, hydroxypropylmethylcellulose, dextrin etc.), a stabilizer(e.g., ascorbic acid, sodium pyrosulfite etc.), a surfactant (e.g.,polysorbate 80, Macrogol etc.), a solubilizer (e.g., glycerine, ethanoletc.), a buffering agent (e.g., phosphoric acid, alkali metal saltthereof, citric acid, alkali metal salt thereof etc.), an isotonicityagent (e.g., sodium chloride, potassium chloride, mannitol, sorbitol,glucose etc.), a pH adjusting agent (hydrochloric acid, sodium hydroxideetc.), a preservative (ethyl p-hydroxybenzoate, benzoic acid,methylparaben, propylparaben, benzyl alcohol etc.), a solubilizer (e.g.,conc. glycerine, meglumine etc.), a solubilizing aid (e.g., propyleneglycol, sucrose etc.), a soothing agent (e.g., glucose, benzyl alcoholetc.) and the like, or into an oil-based injection by dissolving,suspending or emulsifying in a vegetable oil (e.g., olive oil, sesameoil, cottonseed oil, corn oil etc.) or a solubilizing aid such aspropylene glycol etc., and used as an injection.

[0460] An oral formulation can be produced by a method known per se byadmixing the compound (aVa), (aVb), (bX), (bXI) or (cVII), or acombination drug with an excipient (e.g., lactose, sucrose, starch andthe like), a disintegrant (e.g., starch, calcium carbonate and thelike), a binder (e.g., starch, gum arabic, carboxymethyl cellulose,polyvinyl pyrrolidone, hydroxypropyl cellulose and the like) or alubricant (e.g., talc, magnesium stearate, polyethylene glycol 6000 andthe like) and compressing the mixture, optionally followed by a coatingprocess known per se for the purpose of masking a taste, forming anenteric coat, or achieving a sustained release. Such coating may, forexample, be hydroxypropylmethyl cellulose, ethyl cellulose,hydroxymethyl cellulose, hydroxypropyl cellulose, polyoxyethyleneglycol, Tween 80, Pluronic F68, cellulose acetate phthalate,hydroxypropylmethyl cellulose phthalate, hydroxymethyl cellulose acetatesuccinate, Eudragid (ROHME, Germany, a copolymer of methacrylic acid andacrylic acid), a dye (e.g., colcothar, titanium oxide etc.) and thelike. The preparation for oral administration may be either a rapidrelease preparation or a sustained release preparation.

[0461] A suppository can be produced by making the compound (aVa),(aVb), (bX), (bXI) or (cVII), or a combination drug into an oily oraqueous solid, semisolid or liquid composition. Examples of the oilybase to be used for such a composition include glyceride of higher fattyacid (e.g., cacao butter, Witepsol (Dynamit Nobel, Germany etc.), mediumfatty acid (e.g., migliol (Dynamit Nobel, Grmany etc.), vegetable oil(e.g., sesame oil, soybean oil, cottonseed oil etc.) and the like.Examples of the aqueous gel base include natural gums, cellulosederivative, vinyl polymer, acrylate polymer and the like

[0462] Examples of the above-mentioned sustained release preparationinclude sustained release microcapsule and the like.

[0463] A sustained release microcapsule can be prepared by a methodknown per se. For example, a sustained release preparation shown in thefollowing [2] is preferably formed and administered.

[0464] The compound (aVa), (aVb), (bX), (bXI) or (cVII) is preferablyformed into a preparation for oral administration such as a solidpreparation (e.g., powder, granule, tablet, capsule) and the like, or apreparation for rectal administration such as a suppository and thelike. Particularly, a preparation for oral administration is preferable.

[0465] The combination drug can be prepared into the above-mentioneddosage form according to the kind of the drug.

[0466] In the following, [1] an injection of the compound (aVa), (aVb),(bX), (bXI) or (cVII), or a combination drug and preparation thereof,[2] a sustained release preparation or a rapid release preparation ofthe compound (aVa), (aVb), (bX), (bXI) or (cVII), or a combination drugand preparation thereof, and [3] a sublingual tablet, buccal or oralcavity rapid disintegrator of the compound (aVa), (aVb), (bX), (bXI) or(cVII), or a combination drug and preparation thereof are concretelyexplained.

[0467] [1] Injection and Preparation Thereof

[0468] An injection containing the compound (aVa), (aVb), (bX), (bXI) or(cVII), or a combination drug dissolved in water is preferable. Theinjection may contain benzoate and/or salicylate.

[0469] The injection is obtained by dissolving both the compound (aVa),(aVb), (bX), (bXI) or (cVII), or a combination drug and, where desired,benzoate and/or salicylate in water.

[0470] The salt of the above-mentioned benzoic acid and salicylic acidincludes, for example, alkali metal salts such as sodium, potassium andthe like, alkaline earth metal salts such as calcium, magnesium and thelike, ammonium salt, meglumine salt, and organic acid salt such astrometamol and the like, and the like.

[0471] The concentration of the compound (aVa), (aVb), (bX), (bXI) or(cVII), or a combination drug in the injection is about 0.5-50 w/v %,preferably about 3-20 w/v %. The concentration of the benzoate and/orsalicylate is preferably 0.5-50 w/v %, more preferably 3-20 w/v %.

[0472] This agent may contain additives generally used for injections,such as a stabilizer (e.g., ascorbic acid, sodium pyrosulfite etc.), asurfactant (e.g., polysorbate 80, Macrogol etc.), a solubilizer (e.g.,glycerine, ethanol etc.), a buffering agent (e.g., phosphoric acid,alkali metal salt thereof, citric acid, alkali metal salt thereof etc.),an isotonicity agent (e.g., sodium chloride, potassium chloride etc.), adispersing agent (e.g., hydroxypropylmethylcellulose, dextrin), a pHadjusting agent (hydrochloric acid, sodium hydroxide etc.), apreservative (ethyl p-hydroxybenzoate, benzoic acid etc.), a solubilizer(e.g., conc. glycerine, meglumine etc.), a solubilizing aid (e.g.,propylene glycol, sucrose etc.), a soothing agent (e.g., glucose, benzylalcohol etc.) and the like as appropriate. These additives are added ina proportion generally employed for injections.

[0473] The injection is preferably adjusted to pH 2-12, preferably2.5-8.0, by the use of a pH adjusting agent.

[0474] The injection can be obtained by dissolving both the compound(aVa), (aVb), (bX), (bXI) or (cVII), or a combination drug and, wheredesired, benzoate and/or salicylate, and where necessary, theabove-mentioned additives in water. These may be dissolved in any orderin a suitable manner as in conventional roduction of injections.

[0475] The injectable aqueous solution is preferably heated and, in thesame manner as with conventional injections, subjected to, for example,sterilization by filtration, high pressure sterilization by heating andthe like to provide an injection.

[0476] The injectable aqueous solution is preferably subjected to highpressure sterilization by heating at, for example, 100° C.-121° C. for 5min-30 min.

[0477] It may be prepared into an antibacterial solution, so that it canbe used as a preparation for plural subdivided administrations.

[0478] [2] Sustained Release Preparation or Rapid Release Preparationand Preparation Thereof

[0479] A sustained release preparation wherein a core containing thecompound (aVa), (aVb), (bX), (bXI) or (cVII), or a combination drug iscovered on demand with a film forming agent, such as a water-insolublematerial, a swellable polymer and the like, is preferable. For example,a sustained release preparation for oral administration once a day ispreferable.

[0480] The water-insoluble material to be used for the film formingagent is, for example, cellulose ethers such as ethylcellulose,butylcellulose and the like; cellulose esters such as cellulose acetate,cellulose propionate and the like; polyvinyl esters such as poly(vinylacetate), poly(vinyl butyrate) and the like; acrylic polymers such asacrylic acid/methacrylic acid copolymer, methyl methacrylate copolymer,ethoxyethyl methacrylate/cinnamoethyl methacrylate/aminoalkylmethacrylate copolymer, polyacrylic acid, polymethacrylic acid,methacrylic acid alkylamide copolymer, poly(methyl methacrylate),polymethacrylate, polymethacryl amide, aminoalkyl methacrylatecopolymer, poly(methacrylic anhydride) and glycidyl methacrylatecopolymer, particularly Eudragits (Rohm Pharma) such as Eudragit RS-100,RL-100, RS-30D, RL-30D, RL-PO, RS-PO (ethyl acrylate-methylmethacrylate-trimethyl chloride methacrylate-ammonium ethyl copolymer),Eudragit NE-30D (methyl methacrylate-ethyl acrylate copolymer) and thelike, and the like; hydrogenated oils such as hydrogenated castor oil(e.g., Lubri wax (Freund Inc.) and the like) and the like; waxes such ascarnauba wax, fatty acid glycerine ester, paraffin and the like;polyglycerine fatty acid ester and the like.

[0481] As the swellable polymer, a polymer having an acidic dissociablegroup, which shows pH-dependent swelling, is preferable, and a polymerhaving an acidic dissociable group, which shows less swelling in anacidic range, such as in the stomach, but otherwise in a neutral range,such as in the small intestine and large intestine, is preferable.

[0482] Examples of the polymer having an acidic dissociable group, whichshows pH-dependent swelling, include crosslinking type polyacrylic acidpolymers such as Carbomer 934P, 940, 941, 974P, 980, 1342 and the like,polycarbophil, carcium polycarbophil (all mentioned above are theproduct of BF Goodrich), HI-BIS-WAKO 103, 104, 105, 304 (all beingproducts of Waco Pure Chemicals Industries, Ltd.) and the like.

[0483] The film forming agent to be used for the sustained releasepreparation may further contain a hydrophilic material.

[0484] Examples of the hydrophilic material include polysaccharidesoptionally having a sulfuric acid group such as pullulan, dextrin,alkali metal salt of alginic acid and the like; polysaccharides having ahydroxy alkyl group or a carboxy alkyl group such ashydroxypropylcellulose, hydroxypropylmethylcellulose, sodiumcarboxymethylcellulose and the like; methylcellulose,polyvinylpyrrolidone, polyvinyl alcohol, polyethylene glycol and thelike.

[0485] The content of the water-insoluble material of the film formingagent for a sustained release preparation is about 30-about 90% (w/w),preferably about 35-about 80% (w/w), more preferably about 40-75% (w/w),and the content of the swellable polymer is about 3-about 30% (w/w),preferably about 3-about 15% (w/w). The film forming agent may furthercontain a hydrophilic material, in which case the content of thehydrophilic material for film forming agent is not more than about 50%(w/w), preferably about 5-about 40% (w/w), more preferably about 5-about35% (w/w). As used herein, the above-mentioned % (w/w) is a percentagerelative to the film forming agent composition wherein the solvent(e.g., water, lower alcohol such as methanol, ethanol and the like) hasbeen removed from the film forming liquid agent.

[0486] A sustained release preparation is produced by preparing a corecontaining a drug as exemplarily mentioned below, and coating theresulting core with a film forming liquid agent prepared by dissolvingby heating or dissolving or dispersing in a solvent a water-insolublematerial, a swellable polymer and the like.

[0487] I. Preparation of Core Containing a Drug

[0488] The form of the core containing a drug (hereinafter sometimessimply referred to as a core) to be coated with a film forming agent isnot particularly limited, but it is preferably formed into particlessuch as granules, fine granules and the like.

[0489] When the core is made of granules or fine granules, the averageparticle size thereof is preferably about 150-2,000 μm, more preferablyabout 500-about 1,400 μm.

[0490] The core can be prepared by a typical production method. Forexample, a drug is mixed with suitable excipients, binders,disintegrators, lubricants, stabilizers and the like, and subjected towet extrusion granulation, fluidized bed granulation and the like.

[0491] The drug content of the core is about 0.5-about 95% (w/w),preferably about 5.0-about 80% (w/w), more preferably about 30-about 70%(w/w).

[0492] Examples of the excipient to be contained in the core includesaccharides such as sucrose, lactose, mannitol, glucose and the like,starch, crystalline cellulose, calcium phosphate, cornstarch and thelike. Of these, crystalline cellulose and corn starch are preferable.

[0493] Examples of the binder include polyvinyl alcohol,hydroxypropylcellulose, polyethylene glycol, polyvinylpyrrolidone,Pluronic F68, gum arabic, gelatin, starch and the like. Examples of thedisintegrator include carboxymethylcellulose calcium (ECG505),crosscarmellose sodium (Ac-Di-Sol), crosslinked polyvinylpyrrolidone(Crospovidone), low substituted hydroxypropylcellulose (L-HPC) and thelike. Of these, hydroxypropylcellulose, polyvinylpyrrolidone and lowsubstituted hydroxypropylcellulose are preferable. Examples of thelubricant and coagulation preventive include talc, magnesium stearateand inorganic salts thereof, and examples of the lubricant includepolyethylene glycol and the like. Examples of the stabilizer includeacids such as tartaric acid, citric acid, succinic acid, fumaric acid,maleic acid and the like.

[0494] The core can be also prepared by, besides the above-mentionedproduction methods, for example, rolling granulation wherein a drug or amixture of a drug and an excipient, a lubricant and the like is added bysmall portions while spraying a binder dissolved in a suitable solventsuch as water, lower alcohol (e.g., methanol, ethanol and the like) andthe like on an inert carrier particles to be the center of the core, apan coating method, a fluidized bed coating method or a melt granulatingmethod. Examples of the inert carrier particle include those preparedfrom sucrose, lactose, starch, crystalline cellulose and waxes, whichpreferably have an average particle size of about 100 μm-about 1,500 μm.

[0495] To separate the drug contained in the core from the film formingagent, the surface of the core may be coated with a protective agent.Examples of the protective agent include the aforementioned hydrophilicmaterial, water-insoluble material and the like. As the protectiveagent, preferably polyethylene glycol, polysaccharides having a hydroxyalkyl group or a carboxy alkyl group, more preferablyhydroxypropylmethylcellulose and hydroxypropylcellulose are used. Theprotective agent may contain, as a stabilizer, an acid such as tartaricacid, citric acid, succinic acid, fumaric acid, maleic acid and thelike, and a lubricant such as talc and the like. When the protectiveagent is used, the amount to be coated is about 1-about 15% (wlw),preferably about 1-10 about 10% (w/w), more preferably about 2-about 8%(w/w), relative to the core.

[0496] The protective agent can be coated by a typical coating method.Specifically, the protective agent is, for example, spray-coated to thecore by a fluidized bed coating method, a pan coating method, and thelike.

[0497] II. Coating of Core With a Film Forming Agent

[0498] The core obtained in the aforementioned I is coated with a filmforming liquid agent prepared by dissolving by heating or dissolving ordispersing in a solvent the aforementioned water-insoluble material, apH-dependent swellable polymer, and a hydrophilic material to provide asustained release preparation.

[0499] For coating a core with a film forming liquid agent, for example,a spray coating method and the like can be employed.

[0500] The composition ratio of the water-insoluble material, swellablepolymer or hydrophilic material in the film forming liquid agent issuitably determined such that each component of the coating film meetsthe aforementioned content.

[0501] The coating amount of the film forming agent is about 1-about 90%(w/w), preferably about 5-about 50% (w/w), more preferably about 5-35%(w/w), relative to the core (exclusive of the coating amount ofprotective agent).

[0502] As the solvent for the film forming liquid agent, water ororganic solvents can be used alone or in a mixture of the both. Themixing ratio (water/organic solvent: weight ratio) of water and theorganic solvent in the mixture can vary within the range of 1-100%,which is preferably 1-about 30%. The organic solvent is not subject toany particular limitation as long as it dissolves the water-insolublematerial. For example, lower alcohols such as methyl alcohol, ethylalcohol, isopropyl alcohol, n-butyl alcohol and the like, lower alkanonesuch as acetone and the like, acetonitrile, chloroform, methylenechloride and the like are used. Of these, lower alcohol is preferable,and ethyl alcohol and isopropyl alcohol are particularly preferable.Water and a mixture of water and an organic solvent are preferably usedas a solvent of the film forming agent. Where necessary, the filmforming liquid agent may contain an acid such as tartaric acid, citricacid, succinic acid, fumaric acid, maleic acid and the like for thestabilization of the film forming liquid agent.

[0503] When spray coating is employed, the method follows a conventionalcoating method, which specifically includes spray coating the core witha film forming liquid agent by, for example, a fluidized bed coatingmethod, a pan coating method and the like. Where necessary, talc,titanium oxide, magnesium stearate, calcium stearate, light anhydroussilicic acid and the like may be added as a lubricant, and glycerinefatty acid ester, hydrogenated castor oil, triethyl citrate, cetylalcohol, stearyl alcohol and the like may be added as a plasticizer.

[0504] After coating with a film forming agent, an antistatic agent suchas talc and the like may be added as necessary.

[0505] A rapid release preparation may be a liquid (solution,suspension, emulsion and the like) or a solid (particle, pill, tabletand the like). An agent for oral administration, and an agent forparenteral administration, such as injection and the like, are used,with preference given to an agent for oral administration.

[0506] A rapid release preparation may generally contain, in addition tothe drug, which is an active ingredient, carriers, additives andexcipients (hereinafter sometimes simply referred to as excipient)conventionally used in the field of preparation. The excipient for apreparation is not subject to any particular limitation as long as it isconventionally employed as an excipient for a preparation. For example,the excipient for the oral solid preparation includes lactose, starch,corn starch, crystalline cellulose (Asahi Kasei Corporation, AvicelPH101 and the like), powder sugar, granulated sugar, mannitol, lightanhydrous silicic acid, magnesium carbonate, calcium carbonate,L-cysteine and the like, preferably corn starch and mannitol and thelike. These excipients may be used alone or in combination. The contentof the excipient is, for example, about 4.5-about 99.4 w/w %, preferablyabout 20-about 98.5 w/w %, more preferably about 30-about 97 w/w %, ofthe total amount of the rapid release preparation.

[0507] The drug content of the rapid release preparation isappropriately determined from the range of about 0.5-about 95%,preferably about 1-about 60%, of the total amount of the rapid releasepreparation.

[0508] When the rapid release preparation is an oral solid preparation,it generally contains a disintegrator in addition to the above-mentionedcomponents. Examples of the disintegrator include calciumcarboxymethylcellulose (Gotoku Pharmaceutical Co., Ltd., ECG-505),crosscarmellose sodium (e.g., Asahi Kasei Corporation, acjizol),Crospovidone (e.g., colidone CL, BASF), low substitutedhydroxypropylcellulose (Shin-Etsu Chemical Co., Ltd.), carboxymethylstarch (Matsutani Chemical Industry Co., Ltd., sodium carboxymethylstarch (Kimura Sangyo, exprotab), partially a starch (PCS, Asahi KaseiCorporation) and the like. For example, one capable of disintegratinggranules by water absorption, swelling, forming a channel between theactive ingredient constituting the core and an excipient upon contactwith water and the like can be used. These disintegrators can be usedalone or in combination. The amount of the disintegrator isappropriately determined depending on the kind of the combination drugto be used and amount thereof, design of the release preparation and thelike. It is generally about 0.05-about 30 w/w %, preferably about0.5-about 15 w/w %, relative to the total amount of the rapid releasepreparation.

[0509] When the rapid release preparation is an oral preparation, theoral solid preparation may further contain, in addition to theabove-mentioned composition, typical additives used for solidpreparation on demand. Examples of the additive include a binder (e.g.,sucrose, gelatin, gum arabic powder, methylcellulose,hydroxypropylcellulose, hydroxypropylmethylcellulose,carboxymethylcellulose, polyvinylpyrrolidone, Pullulan, dextrin etc.), alubricant (e.g., polyethylene glycol, magnesium stearate, talc, lightanhydrous silicic acid (e.g., Aerosil (Nippon Aerosil)), a surfactant(e.g., anionic surfactant such as sodium alkylsulfate etc., non-ionicsurfactant such as polyoxyethylene fatty acid ester andpolyoxyethylenesorbitan fatty acid ester, polyoxyethylene castor oilderivative etc., and the like), a coloring agent (e.g., tar color,caramel, iron oxide red, titanium oxide, riboflavins), where necessary,a corrigent (e.g., a sweetener, flavor etc.), an absorbent, anantiseptic, a moistening agent, an antistatic agent and the like. As thestabilizer, an organic acid such as tartaric acid, citric acid, succinicacid, fumaric acid and the like may be added.

[0510] Examples of the above-mentioned binder preferably includehydroxypropylcellulose, polyethylene glycol, polyvinylpyrrolidone andthe like.

[0511] The rapid release preparation can be prepared based on theconventional preparation method, by mixing each of the aforementionedcomponents, and where necessary, further kneading and forming. Theabove-mentioned mixing can be performed by a conventional method, suchas mixing, kneading and the like. Specifically, for example, when arapid release preparation is formed into particles, a verticalgranulator, a universal kneader (HATA Tekkohjo), a fluidized bedgranulator FD-5S (Powrex Corporation) and the like are used for mixing,which is followed by granulating by wet extrusion granulation, fluidizedbed granulation and the like, to give the preparation, as in thepreparation of the core of the aforementioned sustained releasepreparation.

[0512] The rapid release preparation and the sustained releasepreparation thus obtained may be used as they are. Alternatively, aftersuitable separate preparation along with an excipient for a preparationand the like according to a conventional method, they may beadministered simultaneously or at optional administration intervals.Alternatively, they may be each prepared into a single preparation fororal administration (e.g., granule, fine granule, tablet, capsule andthe like) as they are or together with excipient for preparation and thelike as appropriate. The both preparations are converted to granules orfine granules and filled in a single capsule and the like to give apreparation for oral administration.

[0513] A Sublingual Tablet, Buccal or Oral Cavity Rapid Disintegratorand Preparation Thereof

[0514] The sublingual tablet, buccal preparation and oral cavity rapiddisintegrator may be a solid preparation such as tablet and the like oran oral cavity mucous membrane adhesion tablet (film).

[0515] As the sublingual tablet, buccal or oral cavity rapiddisintegrator, a preparation containing the compound (aVa), (aVb), (bX)or (bXI), or a combination drug and an excipient is preferable. It maycontain auxiliaries such as a lubricant, an isotonic agent, ahydrophilic carrier, a water dispersible polymer, a stabilizer and thelike. For easy absorption and enhanced bioavailability, β-cyclodextrinor β-cyclodextrin derivative (e.g., hydroxypropyl-β-cyclodextrin and thelike) and the like may be contained.

[0516] Examples of the above-mentioned excipient include lactose,sucrose, D-mannitol, starch, crystalline cellulose, light anhydroussilicic acid and the like. Examples of the lubricant include magnesiumstearate, calcium stearate, talc, colloidal silica and the like,particularly magnesium stearate and colloidal silica are preferable.Examples of the isotonicity agent include sodium chloride, glucose,fructose, mannitol, sorbitol, lactose, saccharose, glycerine, urea andthe like, particularly mannitol is preferable. Examples of thehydrophilic carrier include swellable hydrophilic carriers such ascrystalline cellulose, ethylcellulose, crosslinked polyvinylpyrrolidone,light anhydrous silicic acid, silicic acid, dicalcium phosphate, calciumcarbonate and the like, particularly crystalline cellulose (e.g.,microcrystalline cellulose and the like) is preferable. Examples of thewater dispersible polymer include gum (e.g., gum tragacanth, acacia gum,guar gum), alginate (e.g., sodium alginate), cellulose derivative (e.g.,methylcellulose, carboxymethylcellulose, hydroxymethylcellulose,hydroxypropylcellulose, hydroxypropylmethylcellulose), gelatin, solublestarch, polyacrylic acid (e.g., carbomer), polymethacrylic acid,polyvinyl alcohol, polyethylene glycol, polyvinylpyrrolidone,polycarbofil, ascorbic palmitate and the like, with preference given tohydroxypropylmethylcellulose, polyacrylic acid, alginate, gelatin,carboxymethylcellulose, polyvinylpyrrolidone, polyethylene glycol andthe like. Particularly, hydroxypropylmethylcellulose is preferable.Examples of the stabilizer include cysteine, thiosorbitol, tartaricacid, citric acid, sodium carbonate, ascorbic acid, glycine, sodiumsulfite and the like, particularly, citric acid and ascorbic acid arepreferable.

[0517] The sublingual tablet, buccal and oral cavity rapid disintegratorcan be produced by mixing the compound (aVa), (aVb), (bX) or (bXI), or acombination drug and an excipient by a method known per se. Wheredesired, the above-mentioned auxiliaries such as a lubricant, anisotonic agent, a hydrophilic carrier, a water dispersible polymer, astabilizer, a coloring agent, a sweetener, an antiseptic and the likemay be contained. After mixing the above-mentioned componentssimultaneously or with time staggering, the mixture is compressionformed under pressure to give sublingual tablet, buccal or oral cavityrapid disintegrator. To achieve a suitable hardness, a solvent such aswater, alcohol and the like is used to moisten or wet as necessarybefore and after the compression forming. After the forming, the tabletsmay be dried.

[0518] When a mucous membrane adhesion tablet (film) is produced, thecompound (aVa), (aVb), (bX) or (bXI), or a combination drug and theabove-mentioned water dispersible polymer (preferably,hydroxypropylcellulose, hydroxypropylmethylcellulose), an excipient andthe like are dissolved in a solvent such as water and the like, and theobtained solution is cast to give a film. In addition, an additive suchas a plasticizer, a stabilizer, an antioxidant, a preservative, acoloring agent, a buffer, a sweetener and the like may be added. Toimpart suitable elasticity to the film, glycols such as polyethyleneglycol, propylene glycol and the like may be added, and to increaseadhesion of the film to the oral cavity mucous membrane lining,bioadhesive polymer (e.g., polycarbofil, carbopol) may be added. Thecasting includes pouring the solution on a non-adhesive surface,spreading the solution in a uniform thickness (preferably about 10-1000μ) with a coating tool such as doctor blade and the like and drying thesolution to give a film. The film thus formed may be dried at roomtemperature or under heating and cut into a desired surface area.

[0519] Examples of preferable oral cavity rapid disintegrator are asolid rapid diffusing administration agent having a net structure of thecompound (aVa), (aVb), (bX), (bXI) or (cVII), or a combination drug andwater soluble or water diffusable carrier which are inert to thecompound (aVa), (aVb), (bX), (bXI) or (cVII), or a combination drug. Thenet structure can be obtained by sublimation of a solvent from the solidcomposition consisting of a solution obtained by dissolving the compound(aVa), (aVb), (bX), (bXI) or (cVII), or a combination drug in a suitablesolvent.

[0520] The oral cavity rapid disintegrator preferably contains, inaddition to the compound (aVa), (aVb), (bX), (bXI) or (cVII), or acombination drug, a matrix forming agent and a secondary 15 component.

[0521] Examples of the matrix forming agent include animal proteins orvegetable proteins such as gelatins, dextrins, soybeans, wheat, psylliumseed protein and the like; rubber substances such as gum arabic, guargum, agar, xanthan and the like; polysaccharides; alginic acids;carboxymethylcelluloses; carrageenans; dextrans; pectins; syntheticpolymers such as polyvinylpyrrolidone and the like; a material derivedfrom a gelatin-gum arabic complex and the like. In addition, saccharidessuch as mannitol, dextrose, lactose, galactose, trehalose and the like;cyclic saccharides such as cyclodextrin and the like; inorganic saltssuch as sodium phosphate, sodium chloride, aluminum silicate and thelike; amino acid having 2 to 12 carbon atoms such as glycine, L-alanine,L-aspartic acid, L-glutamine acid, L-hydroxyproline, L-isoleucine,L-leucine, L-phenylalanine and the like are exemplified.

[0522] It is possible to introduce one or more matrix forming agentsinto a solution or suspension before preparation into a solid. Suchmatrix forming agent may exist with a surfactant or without asurfactant. The matrix forming agent can form a matrix, and also canhelp maintain the diffusion of the compound (aVa), (aVb), (bX), (bXI) or(cVII), or a combination drug in the solution or suspension.

[0523] The composition may contain a secondary component such as apreservative, an antioxidant, a surfactant, a thickener, a coloringagent, a pH adjusting agent, a flavor, a sweetener, a taste maskingreagent and the like. Examples of a suitable coloring agent include red,black and yellow ferric oxides and FD&C dyes of Ellis & Everard, such asFD&C blue NO. 2, FD&C red No. 40 and the like. A suitable flavorcontains mint, rasberry, licorice, orange, lemon, grapefruit, caramel,vanilla, cherry, grape flavor and a combination of these. Suitable pHadjusting agent includes citric acid, tartaric acid, phosphoric acid,hydrochloric acid and maleic acid. Suitable sweetener includesaspartame, acesulfame K, thaumatin and the like. Suitable taste maskingagent includes sodium bicarbonate, ion exchange resin, cyclodextrininclusion compound, adsorbent substance and microcapsuled apomorphine.

[0524] As the preparation, one containing the compound (aVa), (aVb),(bX), (bXI) or (cVII), or a combination drug generally in a proportionof about 0.1-about 50 wt %, preferably about 0.1-about 30 wt %, which iscapable of dissolving 90% or more of the compound (aVa), (aVb), (bX),(bXI) or (cVII), or a combination drug in water for about 1 min-about 60min, preferably about 1 min-about 15 min, more preferably about 2min-about 5 min, such as the above-mentioned sublingual tablet, buccaland the like, and an oral cavity rapid disintegrator that disintegrateswithin 1-60 sec, preferably 1-30 sec, more preferably 1-10 sec, afterbeing placed in an oral cavity, are preferable.

[0525] The content of the above-mentioned excipient in the wholepreparation is about 10-about 99 wt %, preferably about 30-about 90 wt%. The content of the β-cyclodextrin or β-cyclodextrin derivativerelative to the whole preparation is 0-about 30 wt %. The content of thelubricant relative to the whole preparation is about 0.01-about 10 wt %,preferably about 1-about 5 wt %. The content of the isotonicity agentrelative to the whole preparation is about 0.1-about 90 wt %, preferablyabout 10-about 70 wt %. The content of the hydrophilic carrier relativeto the whole preparation is about 0.1-about 50 wt %, preferably about10-about 30 wt %. The content of the water dispersible polymer relativeto the whole preparation is about 0.1-about 30 wt %, preferably about10-about 25 wt %. The content of the stabilizer relative to the wholepreparation is about 0.1-about 10 wt %, preferably about 1-about 5 wt %.The above-mentioned preparation may contain additives such as a coloringagent, a sweetener, an antiseptic and the like as necessary.

[0526] While the dose of the combination agent of the present inventionvaries depending on the kind of the compound (aVa), (aVb), (bX), (bXI)or (cVII), the patient's age, body weight and condition, the dosageform, the mode and the period of the treatment, the respective amountsof the compound (aVa), (aVb), (bX), (bXI) or (cVII) and combination drugmay be, for example, about 0.01 to about 1000 mg/kg, preferably about0.01 to about 100 mg/kg, more preferably about 0.1 to about 100 mg/kg,most preferably about 0.1 to about 50 mg/kg, and particularly about 1.5to about 30 mg/kg per day, for a patient (adult weighing about 60 kg)with, for example, breast cancer, said daily dose being givenintravenously once or in several portions during a day. It is a matterof course that a lower daily dose may be sufficient or an excessive dosemay be required since the dose nay vary depending on various factors asdiscussed above.

[0527] The combination drug may be contained in any amount as long as aside effect does not pose a problem. While the daily dose of thecombination drug may vary depending on the disease state, age, sex, bodyweight and difference in sensitivity of the administration object,timing and interval of administration, characteristics, dispensing andkind of the pharmaceutical preparation, the kind of the activeingredient and the like, and is not particularly limited, the amount ofthe drug is generally about 0.001-2000 mg, preferably about 0.01-500 mg,more preferably about 0.1-100 mg, per 1 kg body weight of mammal by oraladministration, which is generally administered once or in 2 to 4portions during a day.

[0528] When the combination agent of the present invention isadministered, it may be administered at the same time. However, acombination drug may be administered first, and then the compound (aVa),(aVb), (bX), (bXI) or (cVII) may be administered. Alternatively, thecompound (aVa), (aVb), (bX), (bXI) or (cVII) may be administered first,and then a combination drug may be administered. For time staggeradministration, the time difference varies depending on the activeingredient to be administered, dosage form and administration route. Forexample, when the combination drug is to be administered first, thecompound (aVa), (aVb), (bX), (bXI) or (cVII) is administered within 1min-3 days, preferably 10 min-1 day, more preferably 15 min-1 hour,after the administration of the combination drug. When the compound(aVa), (aVb), (bX), (bXI) or (cVII) is to be administered first, thecombination drug is administered within 1 min-1 day, preferably 10 min-6hours, more preferably 15 min-1 hour, after the administration of thecompound (aVa), (aVb), (bX), (bXI) or (cVII).

[0529] A preferable administration method includes orally administeringabout 0.001-200 mg/kg of a combination drug prepared into a preparationfor oral administration, and about 15 min later, orally administeringabout 0.005-100 mg/kg of the compound (aVa), (aVb), (bX), (bXI) or(cVII) prepared into a preparation for oral administration as an amountfor the day.

[0530] In addition, the pharmaceutical composition of the presentinvention or the combination agent of the present invention may becombined with a therapy without medicine, such as (1) operation, (2)vasopressor chemotherapy using angiotensin II, (3) gene therapy, (4)thermotherapy, (5) cryotherapy, (6) laser cauterization therapy, (7)radiation therapy and the like.

[0531] For example, the use of the pharmaceutical composition of thepresent invention or the combination agent of the present inventionbefore or after operation, or before or after a combined treatment oftwo or three kinds thereof affords effects such as prevention ofexpression of resistance, prolonged Disease-Free Survival time,suppression of metastasis or recurrence, life prolonging and the like.

[0532] It is also possible to combine a therapy with the pharmaceuticalcomposition of the present invention or the combination agent of thepresent invention, with a supportive therapy such as (i) administrationof antibiotics against complication with various infectious diseases(e.g., β-lactam group such as pansporin, macrolide group such asclarithromycin etc.), (ii) administration of total parenteral nutrition,amino acid preparation, multivitamin preparation for improvement ofmalnutrition, (iii) administration of morphine for relieving pain, (iv)administration of medicine to improve side effects such as nausea,vomition, anorexia, diarrhea, hypoleukocytemia, thrombocytopenia,decreased hemoglobin concentration, alopecia, hepatopathy, nephropathy,DIC, onset of fever and the like, and (v) administration of medicine tosuppress multiple drug resistance in cancer, and the like.

[0533] It is preferable that the pharmaceutical composition of thepresent invention or the combination agent of the present invention beadministered before or after the aforementioned treatment by oraladministration (inclusive of sustained release administration),intravenous administration (inclusive of bolus, infusion and inclusioncompound), subcutaneous or intramuscular injection (inclusive of bolus,infusion, sustained release administration), transdermal, intra-tumorand proximal administrations.

[0534] When the pharmaceutical composition of the present invention orthe combination agent of the present invention is administered beforeoperation, for example, it may be administered once at about 30 min to24 hours before the operation etc., or may be administered at about 3 to6 months before the operation etc. in 1 to 3 cycles. The administrationof the pharmaceutical composition of the present invention or thecombination agent of the present invention before operation decreasessize of, for example, cancer tissues, thereby facilitating the operationetc.

[0535] When the pharmaceutical composition of the present invention orthe combination agent of the present invention is administered afteroperation, for example, it may be repeat administered at about 30 min to24 hours after the operation etc. for several weeks to 3 months. Theadministration of the pharmaceutical composition of the presentinvention or the combination agent of the present invention afteroperation enhances the effect of the operation.

EXAMPLES

[0536] While the present invention is explained in detail in thefollowing by referring to Reference Examples and Examples, the presentinvention is not limited by these Examples.

[0537] The abbreviations used in the description mean the following.

[0538] s: singlet

[0539] d: doublet

[0540] t: triplet

[0541] m: multiplet

[0542] J: coupling constant

[0543] Hz: Hertz

[0544] CDCl₃: Deuterated Chloroform

[0545] DMSO-d₆: Deuterated dimethyl sulfoxide

[0546] D₂O: deuterium oxide

[0547]¹H-NMR: protone nuclear magnetic resonance

[0548] HPLC: high performance liquid chromatography

[0549] Me: methyl

[0550] Room temperature: 15 to 30° C.

[0551]¹H-NMR spectrum was measured by Bruker DPX 300 (300 MHz) typeSpectrometer using tetramethylsilane as an internal standard. All δvalues are shown in ppm.

[0552] HPLC Conditions in Example 4

[0553] column: Inertsil (trademark) ODS-3 (4.6×150 mm I.D.) (GL ScienceInc.)

[0554] mobile phase: 0.05M potassium dihydrogen phosphate

[0555] /acetonitrile=45/55

[0556] wavelength: 254 nm

[0557] temperature: 25° C.

[0558] flow: 1 ml/min

[0559] HPLC Conditions in Reference Example 12, Example 21 and Example22

[0560] column: YMC-Pack ODS-A A-302(150×4.6 mm I.D.) (trademark, YMCCo., Ltd)

[0561] mobile phase: 0.05M potassium dihydrogenphosphate/acetonitrile=45/55

[0562] wavelength: 270 nm

[0563] temperature: 25° C.

[0564] Flow: 1 ml/min

[0565] Powder X ray diffraction was measured using X-ray DiffractometerRINT Ultima+(Rigaku).

Reference Example 1

[0566] Production of 4-chloro-1-(4-methoxyphenyl)-1-butanone

[0567] Anisole (6.75 g, 62.4 mmol) was dissolved in dichloromethane (80ml). The mixture was cooled to −5° C. and aluminum chloride (8.32 g,62.4 mmol) was added. 4-Chlorobutyryl chloride (8.8 g, 62.4 mmol) wasadded dropwise to the mixture at −10° C. and stirred at −10° C. for 1hour. The reaction mixture was poured into iced water (100 ml). Afterseparation, the organic layer was washed with 1N hydrochloric acid (50ml), saturated aqueous sodium hydrogen carbonate (50 ml) and water (50ml), and was concentrated under reduced pressure to give4-chloro-1-(4-methoxyphenyl)-1-butanone (12.7 g). yield 96%.

[0568]¹H-NMR (CDCl₃, δ, 300 MHz) 2.19-2.24(2H,m), 3.13(2H,t,J=7.0 Hz),3.67(2H,t,J=6.2 Hz), 3.87(3H,s), 6.92-6.96(2H,m), 7.94-7.98(2H,m).

Reference Example 2

[0569] Production of 4-chloro-1-(4-methoxyphenyl)-1-butanone

[0570] Anisole (2.16 g, 20 mmol) was dissolved in toluene (20 ml). Themixture was cooled to −10° C. and aluminum chloride (2.67 g, 20 mmol)was added. 4-Chlorobutyryl chloride (2.47 ml, 22 mmol) was addeddropwise at −10° C. and stirred for 0.5 hour at −10° C. The reactionmixture was poured into iced water (40 ml). After separation, theorganic layer was washed with 20% citric acid (10 ml) twice, 1N-sodiumhydroxide (10 ml) and 20% brine (10 ml) twice, and was concentratedunder reduced pressure to give 4-chloro-1-(4-methoxyphenyl)-1-butanone(4.21 g, yield 99%).

Reference Example 3

[0571] Production of 1-(4-chlorobutyl)-4-methoxybenzene

[0572] 4-Chloro-1-(4-methoxyphenyl)-1-butanone (5 g, 23.5 mmol) wasdissolved in tetrahydrofuran (50 ml). 10% Palladium carbon(water-containing product, 500 mg) was added and the mixture wassubjected to catalytic reduction under hydrogen pressure (0.8 MPa, 50°C. for 3 h). The catalyst was filtered off and the filtrate wasconcentrated under reduced pressure to give1-(4-chlorobutyl)-4-methoxybenzene (4.6 g, yield 99%).

[0573]¹H-NMR (CDCl₃, δ, 300 MHz) 1.69-1.83(4H,m), 2.59(2H,t,J=7.4 Hz),3.54(2H,t,J=6.2 Hz), 3.79(3H,s), 6.81-6.85(2H,m), 7.08-7.11(2H,m).

Example 1

[0574] Production of 1-[4-(4-methoxyphenyl)butan-1-yl]-1H-1,2,3-triazolemethanesulfonate

[0575] 1-(4-Chlorobutyl)-4-methoxybenzene (950 mg, 4.78 mmol),1H-1,2,3-triazole (660 mg, 9.55 mmol) and potassium iodide (793 mg, 4.78mmol) were added to t-butanol (5 ml). Sodium hydroxide (382 mg, 9.55mmol) was added and the mixture was refluxed under heating for 11 hours.After cooling to room temperature, toluene and water were added and themixture was partitioned. The organic layer was washed successively withwater, 20% citric acid, saturated aqueous sodium hydrogen carbonate andwater, and was concentrated under reduced pressure. To the residue wereadded ethyl acetate (6 ml) and isopropyl ether (3 ml). Methanesulfonicacid (402 mg, 4.18 mmol) was added at room temperature. Ethylacetate/isopropyl ether=2/1 (2 ml) was added and the mixture was stirredat room temperature for 30 min. The precipitated crystals were collectedby filtration and dried under reduced pressure to give1-[4-(4-methoxyphenyl)butan-1-yl]-1H-1,2,3-triazole methanesulfonate(1.14 g, yield 73%).

[0576]¹H-NMR (DMSO-d₆, δ, 300 MHz) 1.40-1.51(2H,m), 1.74-1.84(2H,m)2.39(3H,s), 2.51(2H,t,J=7.7 Hz), 3.69(3H,s), 4.38(2H,t,J=7.0 Hz),6.79-6.84(2H,m), 7.04-7.09(2H,m), 7.71(1H,d,J=0.7 Hz), 8.11(1H,d,J=0.7Hz)

Example 2

[0577] Production of 1-[4-(4-methoxyphenyl)butan-1-yl]-1H-1,2,3-triazolemethanesulfonate

[0578] To 1-(4-Chlorobutyl)-4-methoxybenzene (2468 mg, 12.42 mmol) wasadded 2-methyl-2-butanol (5 ml), and then 1H-1,2,3-triazole (1286 mg,18.62 mmol) and potassium iodide (2062 mg, 14.24 mmol) were added.Sodium hydroxide (745 mg, 18.62 mmol) was added and the mixture wasrefluxed under heating for 4 hours. After cooling to room temperature,toluene and water were added and the mixture was partitioned. Theorganic layer was washed with water, 20% citric acid (twice), saturatedaqueous sodium hydrogen carbonate and water (twice). The organic layerwas concentrated under reduced pressure. To the residue was added ethylacetate and the mixture was concentrated under reduced pressure. Ethylacetate (20 ml) and isopropyl ether (10 ml) were added and then seedcrystal was added. Methanesulfonic acid (1021 mg, 10.62 mmol) was addeddropwise while keeping the mixture at 20-30° C. The mixture was stirredat 20-30° C. for 1 hour. The precipitated crystals were collected byfiltration and washed with ethyl acetate/isopropyl ether=1/1. Thecrystals were dried under reduced pressure to give1-[4-(4-methoxyphenyl)butan-1-yl]-1H-1,2,3-triazole methanesulfonate(3.04 g) as white crystals (yield 75%).

[0579]¹H-NMR (DMSO-d₆, δ, 300 MHz) 1.40-1.51(2H,m), 1.74-1.84(2H,m),2.39(3H,s), 2.51(2H,t,J=7.7 Hz), 3.69(3H,s), 4.38(2H,t,J=7.0 Hz),6.79-6.84(2H,m), 7.04-7.09(2H,m), 7.71(1H,d,J=0.7 Hz), 8.11(1H,d,J=0.7Hz).

Example 3

[0580] Production of 1-[4-(4-methoxyphenyl)butan-1-yl]-1H-1,2,3-triazolehydrochloride

[0581] 1-(4-Chlorobutyl)-4-methoxybenzene (993 mg, 5 mmol),1H-1,2,3-triazole (691 mg, 10 mmol), potassium iodide (830 mg, 5 mmol)and lithium chloride (424 mg, 10 mmol) were added to t-butanol (5 ml),and t-butoxysodium (961 mg, 10 mmol) was added. The mixture was refluxedunder heating for 17 hours. After cooling to room temperature, tolueneand water were added and the mixture was partitioned. The organic layerwas washed with water, 20% citric acid (three times), saturated aqueoussodium hydrogen carbonate and water, and concentrated under reducedpressure. To the residue was added ethanol (30 ml). Concentratedhydrochloric acid (2 ml) was added and the mixture was concentratedunder reduced pressure. To the residue was added 2-propanol, and afterconcentration under reduced pressure, ethyl acetate was added. Themixture was concentrated under reduced pressure and ethyl acetate (3 ml)was added. The mixture was stirred at room temperature for 45 min. Theprecipitated crystals were collected by filtration and dried underreduced pressure to give1-[4-(4-methoxyphenyl)butan-1-yl]-1H-1,2,3-triazole hydrochloride (772mg, yield 58%).

[0582]¹H-NMR (DMSO-d₆, δ, 300 MHz) 1.39-1.50(2H,m), 1.73-1.83(2H,m)2.49(2H,t,J=7.6 Hz), 3.68(3H,s), 4.37(2H,t,J=7.0 Hz), 6.77-6.83(2H,m),7.02-7.07(2H,m), 7.73(1H,d,J=0.7 Hz), 8.13(1H,d,J=0.7 Hz).

Example 4

[0583] Production of 1-[4-(4-methoxyphenyl)butan-1-yl]-1H-1,2,3-triazole

[0584] 1-(4-Chlorobutyl)-4-methoxybenzene (993 mg, 5 mmol),1H-1,2,3-triazole (691 mg, 10 mmol) and potassium iodide (830 mg, 5.0mmol) were dissolved in dimethylformamide (5 ml) and the mixture wasstirred at 100° C. for 2.5 hours. After cooling the reaction mixture toroom temperature, ethyl acetate and water were added, and the mixturewas partitioned. The organic layer was measured by HPLC. As a result,1-[4-(4-methoxyphenyl)butan-1-yl]-1H-1,2,3-triazole (550 mg) was foundto be present (yield 48%).

Reference Example 4

[0585] Production of 4-[4-(1H-1,2,3-triazol-1-yl)butyl]phenol

[0586] 1-[4-(4-Methoxyphenyl)butan-1-yl]-1H-1,2,3-triazolemethanesulfonate (4.0 g, 12.22 mmol) was added into 48% hydrobromic acid(8 ml) and the mixture was heated at 80-90° C. for 6 hours. The reactionmixture was ice-cooled and 4N-sodium hydroxide (32 ml) was addeddropwise. The mixture was washed with toluene. 6N Hydrochloric acid wasadded to the aqueous layer to adjust pH to 6.3. The mixture wasextracted with ethyl acetate (30 ml) and tetrahydrofuran (15 ml) andthen washed with water. Activated carbon (200 mg) was added and themixture was stirred at room temperature for 10 min. The mixture wasfiltrated and concentrated under reduced pressure. To the residue wasadded ethyl acetate (10 ml), and the mixture was refluxed. Afterallowing to cool and stirring for 30 min, hexane (10 ml) was added andthe mixture was stirred at room temperature for 30 min. The precipitatedcrystals were collected by filtration and dried under reduced pressureto give 4-[4-(1H-1,2,3-triazol-1-yl)butyl]phenol (2.25 g, yield 85%).

[0587]¹H-NMR (CDCl₃-DMSO-d₆, δ, 300 MHz) 1.48-1.59(2H,m),1.80-1.91(2H,m), 2.49(2H,t,J=7.5 Hz), 4.31(2H,t,J=7.2 Hz),6.68-6.73(2H,m), 6.87-6.91(2H,m), 7.45(1H,d,J=0.7 Hz), 7.61(1H,d,J=0.7Hz), 8.12(1H,s).

Reference Example 5

[0588] Production of 4-(trifluoromethyl)cinnamamide

[0589] 4-(Trifluoromethyl)cinnamic acid (64.85 g, 300 mmol) was added totoluene (325 ml) and dimethylformamide (2.2 ml). Thionyl chloride (26.3ml, 361 mmol) was added dropwise at room temperature. The mixture washeated at 45° C. for 2 hours. The obtained reaction mixture was addeddropwise to 25% aqueous ammonia (325 ml) while keeping the mixture at5-20° C. The mixture was stirred at room temperature for 1 hour. Thecrystals were filtered, washed with water and isopropyl ether and driedunder reduced pressure to give 4-(trifluoromethyl)cinnamamide (60.76 g,yield 94%).

[0590]¹H-NMR (CDCl₃-DMSO-d₆, δ, 300 MHz) 5.93(1H,s), 6.53(1H,d,J=15.8Hz), 6.75(1H,s), 7.48-7.53(5H,m).

Reference Example 6

[0591] Production of4-(chloromethyl)-2-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]-1,3-oxazole

[0592] 4-(Trifluoromethyl)cinnamamide (1 g, 4.65 mmol) and1,3-dichloroacetone (1.1 g, 8.66 mmol) were added to toluene (5 ml) andthe mixture was refluxed under heating for 8 hours. Ethyl acetate (20ml) was added and the mixture was washed with water (20 ml) twice, andthen concentrated under reduced pressure. To the residue was addedmethanol (4 ml) and the mixture was stirred at room temperature. Thecrystals were filtrated and dried under reduced pressure to give4-(chloromethyl)-2-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]-1,3-oxazole(733 mg, yield 55%).

[0593]¹H-NMR (CDCl₃, δ, 300 MHz) 4.56(2H,s), 7.01(1H,d,J=16.4 Hz),7.54-7.68(6H,m).

Reference Example 7

[0594] Production of[1-[4-[4-[[2-[(E)-2-(4-trifluoromethyl)phenyl]-ethenyl]-1,3-oxazol-4-yl]methoxy]phenyl]butyl]-1H-1,2,3-triazole

[0595] 4-[4-(1H-1,2,3-Triazol-1-yl)butyl]phenol (400 mg, 1.84 mmol) and4-(chloromethyl)-2-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]-1,3-oxazole(529 mg, 1.84 mmol) were dissolved in dimethylformamide (3 ml) andpotassium carbonate (279 mg, 2.02 mmol) was added. The mixture wasstirred at 65-75° C. for 4 hours.4-[4-(1H-1,2,3-Triazol-1-yl)butyl]phenol (40 mg, 0.184 mmol) was addedand the mixture was stirred at 65-75° C. for further 3 hours. Themixture was cooled to room temperature and water (5 ml) was added, thenmethanol (3 ml) was added. The mixture was stirred at room temperaturefor 40 min, and the precipitated crystals were collected by filtrationand washed with water. The crystals were dried under reduced pressure togive[1-[4-[4-[[2-[(E)-2-(4-trifluoromethylphenyl)ethenyl]-1,3-oxazol-4-yl]methoxy]phenyl]butyl]-1H-1,2,3-triazole(799 mg, yield 93%).

[0596]¹H-NMR (CDCl₃, δ, 300 MHz) 1.57-1.68(2H,m), 1.88-1.99(2H,m),2.60(2H,t,J=7.5 Hz), 4.39(2H,t,J=7.1 Hz), 5.01(2H,s), 6.89-7.08(5H,m),7.49-7.70(8H,m).

Example 5

[0597] Production of 4-[4-(tert-butoxy)phenyl]butyl methanesulfonate

[0598] To the kolben were added 4-[4-(tert-butoxy)phenyl-butan-1-ol (70g), triethylamine (65.2 ml) and ethyl acetate (720 ml), and the mixturewas stirred. The mixture was cooled to 10° C. and methanesulfonylchloride (53.8 g) was dropwise. The mixture was stirred for 1 hour whilekeeping it at 5-17° C. Water (300 ml) was added and the mixture wasstirred, left standing and partitioned. The organic layer was washedsuccessively with 5% aqueous sodium hydrogen carbonate (300 ml) andwater (300 ml). The organic layer was concentrated under reducedpressure to give the objective compound (102.2 g) as a concentratedresidue.

[0599]¹H-NMR (CDCl₃, 300 MHz) ppm: 1.33(9H,s), 1.6-1,8(4H,m), 2.62(2H,t, J=7.1), 2.99(3H,s), 4.24(2H,t,J=6.1), 6.91(2H,d,J=8.5 Hz),7.05(2H,d,J=8.5 Hz)

Reference Example 8

[0600] Production of 1-tert-butoxy-4-(4-iodobutyl)benzene

[0601] To the kolben were added 4-[4-(tert-butoxy)phenyl]butylmethanesulfonate (33.66 g), sodium iodide (22.49 g) and acetone (337ml), and the mixture was reacted for 1 hour by reflux under heating. Tothe reaction mixture were added water (500 ml) and diisopropyl ether(500 ml). After stirring, the mixture was left standing and partitionedto separate the organic layer. The organic layer was washed successivelywith saturated aqueous sodium hydrogen carbonate (250 ml), 10% hypo (250ml) twice and water (250 ml). The organic layer was concentrated underreduced pressure to give the objective compound (35.8 g) as aconcentrated residue.

[0602]¹H-NMR (CDCl₃, 300 MHz) ppm: 1.33(9H,s), 1.6-1.7(2H,m),1.8-1.9(2H,m), 2.59(2H,t,J=7.5 Hz), 3.20(2H,t,J=6.9 Hz), 6.90(2H,d,J=8.4Hz), 7.04(2H,d,J=8.4 Hz)

Example 6

[0603] Production of 4-[4-(tert-butoxy)phenyl]butyl(4-methylbenzene)sulfonate

[0604] To the kolben were added 4-[4-(tert-butoxy)phenyl-butan-1-ol(5.28 g) and pyridine (9 ml), and the mixture was stirred.Toluenesulfonyl chloride (5.70 g, 1.5 eq) was added at an innertemperature of 5° C. and the mixture was allowed to react at roomtemperature for 2 hours. Water (20 ml) was added at not higher than 10°C. and the mixture was stirred for 5 min. Ethyl acetate (40 ml) wasadded and the aqueous layer was separated. The organic layer was washedwith 10% aqueous boric acid (20 ml) three times and with water (20 ml)once. The organic layer was concentrated under reduced pressure to givea concentrated residue (8.80 g) of the objective compound.

[0605] This was applied to silica gel chromatography and the effectivefraction was concentrated to give the objective compound (6.40 g).

[0606]¹H-NMR (CDCl₃, 300 MHz) ppm: 1.32(9H,s), 1.5-1.7(4H,m),2.45(3H,s), 2.52(2H,t,J=7.1 Hz), 4.04(2H,t,J=6.0 Hz), 6.87(2H,d,J=8.5Hz), 6.98(2H,d,J=8.5 Hz), 7.33(2H,d,J=8.1 Hz), 7.78(2H,d,J=8.1 Hz)

Example 7

[0607] Production of 1-tert-butoxy-4-(4-chlorobutyl)benzene

[0608] To a solution of 4-[4-(tert-butoxy)phenyl-butan-1-ol (44.7 g),toluene (220 ml) and triethylamine (30.4 g) was added dropwise thionylchloride (28.6 g) at an inner temperature 60° C. over about 2 hours, andthe mixture was reacted for 4 hours. Water (90 ml) was added to separatethe organic layer. The organic layer was washed with 5% sodium hydrogencarbonate (90 ml) and water (90 ml), and dried over anhydrous magnesiumsulfate. The organic layer was concentrated and evaporated under reducedpressure (128-130° C./0.2 mmHg) to give the objective compound (34.3 g).

[0609] 1H-NMR (CDCl₃, 300 MHz) ppm: 1.32(9H,s), 1.7-1.8(4H,m)2.60(2H,t,J=7.2 Hz), 3.55(2H,t,J=6.2), 6.90(2H,d,J=8.4 Hz),7.06(2H,d,J=8.4 Hz)

Example 8

[0610] Production of 1-tert-butoxy-4-(4-chlorobutyl)benzene

[0611] To the kolben were added 4-[4-(tert-butoxy)phenyl-butan-1-ol (5.0g) and pyridine (15 ml), and the mixture was stirred. To the mixture wasadded dropwise methanesulfonyl chloride (3.84 g) under ice-cooling. Themixture was heated to about 60° C. and reacted for 2 hours. To thereaction mixture were added toluene (25 ml) and water (25 ml), and themixture was stirred, left standing and partitioned. The organic layerwas washed with water (25 ml) twice. The organic layer was concentratedto give the objective compound (4.27 g) as a concentrated residue.

Example 9

[0612] Production of1-[4-(4-tert-butoxyphenyl)butan-1-yl]-1H-1,2,3-triazole

[0613] To the kolben were added 1H-1,2,3-triazole (5.18 g), sodiumiodide (7.49 g), sodium hydroxide (3.0 g) and 2-methyl-2-butanol (20ml), and the mixture was refluxed under heating for 1 hour (innertemperature then was 100-102° C.). A solution of4-[4-(tert-butoxy)phenyl]butyl methanesulfonate (15.09g)/2-methyl-2-butanol (20 ml) was added dropwise over about 1 hour 40min. The mixture was reacted at the same temperature for 3 hours. Aftercooling, the mixture was concentrated. To the residue were added water(20 ml) and toluene (20 ml), and the mixture was stirred. After standingand partitioning, the organic layer was washed with 5% aqueous sodiumhydrogen carbonate (20 ml) and then with water (20 ml). The organiclayer was concentrated to give objective compound (12.72 g) as aconcentrated residue.

[0614]¹H-NMR (CDCl₃, 300 MHz) ppm: 1.35(9H,s), 1.6-1.7(2H,m),1.9-2.0(2H,m), 2.63(2H,t,J=7.6 Hz), 4.41(2H,t,J=7.1 Hz), 6.91(2H,d,J=8.5Hz), 7.04(2H,d,J=8.5),7.51(1H,d,J=0.8), 7.71(1H,d,J=0.8)

Example 10

[0615] Production of1-[4-(4-tert-butoxyphenyl)butan-1-yl]-1H-1,2,3-triazole

[0616] To the kolben were added sodium hydroxide (3.0 g),1H-1,2,3-triazole (5.18 g) and 2-methyl-2-butanol (20 ml), and themixture was refluxed under heating for 1 hour (inner temperature thenwas 100-102° C.). A solution of 1-tert-butoxy-4-(4-iodobutyl)benzene(17.9 g)/2-methyl-2-butanol (20 ml) was added dropwise over about 1 hour50 min. The mixture was reacted at the same temperature for 3 hours.After cooling, the mixture was concentrated. To the residue were addedwater (20 ml) and toluene (20 ml), and the mixture was stirred. Afterstanding and partitioning, the organic layer was washed with 5% aqueoussodium hydrogen carbonate (20 ml) and then with water (20 ml). Theorganic layer was concentrated to give objective compound (15.6 g) as aconcentrated residue.

Example 11

[0617] Production of1-[4-(4-tert-butoxyphenyl)butan-1-yl]-1H-1,2,3-triazole

[0618] To the kolben were added 1H-1,2,3-triazole (1.65 g), sodiumiodide (3.58 g), sodium hydroxide (0.96 g) and 2-methyl-2-butanol (7ml), and the mixture was refluxed under heating for 1 hour (innertemperature then was 100-102° C.). A solution of4-[4-(tert-butoxy)phenyl]butyl (4-methylbenzene)phosphonate 6.00g/2-methyl-2-butanolml was added dropwise over about 1 hour. The mixturewas reacted at the same temperature for 3 hours. After cooling, themixture was concentrated. To the residue were added water (10 ml) andtoluene (20 ml), and the mixture was stirred. After standing andpartitioning, the organic layer was washed with 5% aqueous sodiumhydrogen carbonate (10 ml) and then with water (10 ml). The organiclayer was concentrated to give objective compound (4.10 g) asconcentrated residue.

Example 12

[0619] Production of1-[4-(4-tert-butoxyphenyl)butan-1-yl]-1H-1,2,3-triazole

[0620] To the kolben were added 1H-1,2,3-triazole (5.18 g), sodiumiodide (7.48 g), sodium hydroxide (3.0 g) and 2-methyl-2-butanol (20ml), and the mixture was refluxed under heating for 1 hour. A solutionof 1-tert-butoxy-4-(4-chlorobutyl)benzene (12.04 g)/2-methyl-2-butanol(20 ml) was added dropwise over about 2 hours, and the mixture wasreacted at inner temperature 100-102° C. for 2 hours. Water (20 ml) andtoluene (20 ml) was added and the mixture was stirred, left standing andpartitioned to separate the aqueous layer. The organic layer was washedsuccessively with 5% aqueous sodium hydrogen carbonate (20 ml) and water(20 ml). The organic layer was concentrated to give the objectivecompound (13.55 g) as a concentrated residue.

Reference Example 9

[0621] Production of 4-[4-(1H-1,2,3-triazol-1-yl)butyl]phenol

[0622] To the kolben were added1-[4-(4-tert-butoxyphenyl)butan-1-yl]-1H-1,2,3-triazole (10.0 g) and4N-hydrochloric acid (40 ml), and the mixture was reacted at 49-52° C.for 1 hour. After completion of the reaction, 30% sodium hydroxide (18ml) was added and the mixture was extracted with ethyl acetate (100 ml).The organic layer was washed with 5% aqueous sodium hydrogen carbonate(50 ml) and water (50 ml), and the organic layer was concentrated todryness. To the concentrated residue was added ethyl acetate (15 ml) andthe mixture was refluxed under heating for about 30 min. The mixture wasallowed to cool with stirring for 1 hour, and stirred at 5-10° C. for 1hour. The precipitated crystals were collected by filtration and washedwith cold-ethyl acetate (2.5 ml).

[0623] Wet crystals were dried under reduced pressure at an outertemperature of 40° C. to give 4-[4-(1H-1,2,3-triazol-1-yl)butyl]phenol(5.51 g).

Reference Example 10

[0624] Production of 4-[4-(1H-1,2,3-triazol-1-yl)butyl]phenol

[0625] To the kolben were added1-[4-(4-tert-butoxyphenyl)butan-1-yl]-1H-1,2,3-triazole (10.0 g) and4N-hydrochloric acid (40 ml), and the mixture was heated to about 50° C.and reacted for 1 hour. The reaction mixture was adjusted to pH 2.5 with30% aqueous sodium hydroxide, and extracted with ethyl acetate (140 ml).The organic layer was washed successively with saturated sodium hydrogencarbonate (50 ml) and water (50 ml), and the organic layer wasconcentrated. To the residue was added ethyl acetate (20 ml) and themixture was heated-under reflux to dissolve the residue, which was thenallowed to cool to allow crystallization. The mixture was cooled toabout 5° C. and stirred for 1 hour. The precipitated crystals werecollected by filtration and washed with cold-ethyl acetate (25 ml). Wetcrystals were dried to give the objective compound (6.14 g).

Example 13

[0626] Production of 1-(4-phenylbutyl)-1H-1,2,3-triazole

[0627] 1,2,3-Triazole (1623 mg, 23.5 mmol), sodium iodide (2353 mg, 15.7mmol) and sodium hydroxide (940 mg, 23.5 mmol) were added to t-amylalcohol (6.2 ml), and the mixture was refluxed under stirring for 1hour. 1-Chloro-4-phenylbutane (2648 mg, 15.7 mmol) was dissolved int-amyl alcohol (6.2 ml) and added dropwise under reflux over 1 hour. Themixture was refluxed under stirring for 2 hours and cooled to roomtemperature, and toluene (50 ml) was added. The mixture was washed withwater (50 ml×2), dried over anhydrous sodium sulfate and concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography (hexane/ethyl acetate=4/1→1/3) to give1-(4-phenylbutyl)-1H-1,2,3-triazole (2.56 g) as colorless oil. yield81%. 2-(4-Phenylbutyl)-2H-1,2,3-triazole (360 mg) was obtained as acolorless oil (yield 11%).

[0628] 1-(4-phenylbutyl)-1H-1,2,3-triazole

[0629]¹H-NMR (CDCl₃, δ, 300 MHz) 1.59-1.70(2H,m), 1.87-2.00(2H,m)2.65(2H,t,J=7.54 Hz), 4.39(2H,t,J=7.12 Hz), 7.12-7.30(5H,m), 7.50(1H,s),7.69(1H,s)

[0630] 2-(4-phenylbutyl)-2H-1,2,3-triazole

[0631]¹H-NMR (CDCl₃, δ, 300 MHz) 1.58-1.67(2H,m), 1.96-2.07(2H,m),2.65(2H,t,J=7.63 Hz), 4.47(2H,t,J=7.04 Hz), 7.13-7.30(5H,m), 7.59(2H,s).

Example 14

[0632] Production of 1-(2-phenylethyl)-1H-1,2,3-triazole

[0633] 1,2,3-Triazole (1634 mg, 23.7 mmol), sodium iodide (2364 mg, 15.8mmol), sodium hydroxide (946 mg, 23.7 mmol) were added to t-amyl alcohol(6.2 ml), and the mixture was refluxed under stirring for 1 hour.1-Chloro-2-phenylethane (2217 mg, 15.8 mmol) was dissolved in t-amylalcohol (6.2 ml) and added dropwise under reflux over 1 hour. Themixture was refluxed under stirring for 3.5 hours. The mixture wascooled to room temperature and toluene (50 ml) was added. The mixturewas washed with water (50 ml×2), dried over anhydrous sodium sulfate andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (hexane/ethyl acetate=3/1→1/3) to give1-(2-phenylethyl)-1H-1,2,3-triazole as a colorless oil (2.0 g, yield73%). 2-(2-Phenylethyl)-2H-1,2,3-triazole (315 mg) was obtained as acolorless oil (yield 12%).

[0634] 1-(4-phenylethyl)-1H-1,2,3-triazole

[0635]¹H-NMR (CDCl₃, δ, 300 MHz) 3.32(2H,t,J=7.20 Hz), 4.62(2H,t,J=7.17Hz), 7.07-7.11(2H,m), 7.21-7.32(4H,m), 7.61(1H,s).

[0636] 2-(4-phenylethyl)-2H-1,2,3-triazole

[0637]¹H-NMR (CDCl₃, δ, 300MHz) 3.28(2H,t,J=7.79 Hz), 4.68(2H,t,J=7.60Hz), 7.15-7.32(5H,m), 7.59(2H,s).

Example 15

[0638] Production of 1-phenyl-2-(1H-1,2,3-triazol-1-yl)ethanone

[0639] 1,2,3-Triazole (1689 mg, 24.45 mmol), sodium iodide (2443 mg,16.3 mmol) and sodium hydroxide (978 mg, 24.45 mmol) were added tot-amyl alcohol (6.5 ml), and the mixture was refluxed under stirring for1 hour. 2-Chloro-1-phenylethanone (2520 mg, 16.3 mmol) was dissolved int-amyl alcohol (13 ml) and added dropwise over 1 hour. The mixture wasrefluxed under stirring for 1 hour. The mixture was cooled to roomtemperature, toluene (50 ml) was added. The mixture was washed withwater (50 ml×2), dried over anhydrous sodium sulfate and concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography (hexane/ethyl acetate=3/2→1/4) to give1-phenyl-2-(1H-1,2,3-triazol-1-yl)ethanone (1.38 g) as brown crystals(yield 45%). 1-Phenyl-2-(2H-1,2,3-triazol-2-yl)ethanone (550 mg) wasobtained as yellow crystals (yield 18%).

[0640] 1-phenyl-2-(1H-1,2,3-triazol-1-yl)ethanone

[0641]¹H-NMR (CDCl₃, δ, 300 MHz) 5.91(2H,s), 7.52-7.58(2H,m),7.65-7.69(1H,m), 7.74(1H,d,J=0.95 Hz), 7.80(1H,d,J=0.95 Hz),7.99-8.03(2H,m).

[0642] 1-phenyl-2-(2H-1,2,3-triazol-2-yl)ethanone

[0643]¹H-NMR (CDCl₃, δ, 300 MHz) 5.92(2H,s), 7.49-7.55(2H,m),7.62-7.66(1H,m), 7.74(2H,s), 7.95-7.99(2H,m).

Example 16

[0644] Production of 1-benzyl-1H-1,2,3-triazole

[0645] 1,2,3-Triazole (1523 mg, 22.05 mmol), sodium iodide (2203 mg,14.7 mmol) and sodium hydroxide (882 mg, 22.05 mmol) were added tot-amyl alcohol (5.8 ml), and the mixture was refluxed under stirring for1 hour. Benzyl chloride (1861 mg, 14.7 mmol) was dissolved in t-amylalcohol (5.8 ml) and added dropwise under reflux over 1 hour. Themixture was refluxed under stirring for 1 hour. The mixture was cooledto room temperature and toluene (50 ml) was added. The mixture waswashed with water (50 ml×2), dried over anhydrous sodium sulfate andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (hexane/ethyl acetate=3/1→1/3) to give1-benzyl-1H-1,2,3-triazole (2.10 g) as white crystals, yield 90%, and2-benzyl-2H-1,2,3-triazole (140 mg) as white crystals (yield 6%).

[0646] 1-benzyl-1H-1,2,3-triazole

[0647]¹H-NMR (CDCl₃, δ, 300 MHz) 5.56(2H,s), 7.24-7.28(2H,m),7.33-7.40(3H,m), 7.47(1H,s),7.70(1H,s).

[0648] 2-benzyl-2H-1,2,3-triazole

[0649]¹H-NMR (CDCl_(3, δ, 300) MHz) 5.61(2H,s), 7.26-7.35(5H,m),7.63(2H,s).

Example 17

[0650] Production of 1-(1-naphthylmethyl)-1H-1,2,3-triazole

[0651] 1,2,3-Triazole (1454 mg, 21.05 mmol), sodium iodide (2103 mg,14.03 mmol) and sodium hydroxide (842 mg, 21.05 mmol) were added tot-amyl alcohol (5.5 ml), and the mixture was refluxed under stirring for1 hour. 1-(Chloromethyl)naphthalene (2478 mg, 14.03 mmol) was dissolvedin t-amyl alcohol (5.5 ml) and added dropwise under reflux over 1 hour.The mixture was refluxed under stirring for 1 hour. The mixture wascooled to room temperature and toluene (50 ml) was added. The mixturewas washed with water (50 ml×2), dried over anhydrous sodium sulfate andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (hexane/ethyl acetate=2/1→1/3) to give1-(1-naphthylmethyl)-1H-1,2,3-triazole (2.47 g) as white crystals (yield84%), and 2-(1-naphthylmethyl)-2H-1,2,3-triazole as a colorless oil (136mg, yield 5%).

[0652] 1-(1-naphthylmethyl)-1H-1,2,3-triazole

[0653]¹H-NMR (CDCl₃, δ, 300 MHz) 6.02(2H,s), 7.33(1H,s),7.41-7.55(4H,m), 7.64(1H,s), 7.89-7.97(3H,m).

[0654] 2-(1-naphthylmethyl)-2H-1,2,3-triazole

[0655]¹H-NMR (CDCl₃, δ, 300 MHz) 6.06(2H,s),7.41-7.57(4H,m), 7.62(2H,s),7.84-7.89(2H,m), 8.15(1H,d,J=7.96 Hz).

Reference Example 11

[0656] Production of 2,2-dichloroacetaldehyde tosylhydrazone

[0657] Tosylhydrazine (234 g, 1.26 mol) was suspended in propionic acid(2 L) and dichloroacetaldehyde (142 g, 1.26 mol) was added at 15-20° C.The mixture was stirred at room temperature for 2 hours and underice-cooling for 3 hours. The precipitated crystals were collected byfiltration and washed with toluene. The crystals were dried underreduced pressure to give 2,2-dichloroacetaldehyde tosylhydrazone (247 g,yield 70%).

[0658]¹H-NMR (CDCl₃, δ, 300 MHz) 2.47(3H,s), 6.12(1H,d,J=7.4 Hz)7.21(1H,d,J=7.4 Hz), 7.34-7.38(2H,m), 7.80-7.84(2H,m), 8.06(1H,s).

Reference Example 12

[0659] Production of 1-[4-(4-methoxyphenyl)butan-1-yl]-1H-1,2,3-triazole

[0660] 1-(4-Aminobutyl)-4-methoxybenzene hydrochloride (1.0 g, 4.64mmol) was dissolved in water. Toluene and 2N-sodium hydroxide (10 ml)were added and the mixture was partitioned. The mixture was washed with20% brine, dried over anhydrous sodium sulfate and concentrated underreduced pressure. The residue was dissolved in methanol (8 ml) and thesuspension of 2,2-dichloroacetaldehyde tosylhydrazone (2.61 g, 9.28mmol) in methanol (12 ml) was added dropwise at 15-20° C., and themixture was stirred at room temperature for 2 hours. Methanol was addedand, after making the mixture homogeneous, it was quantitativelymeasured by HPLC. As a result,1-[4-(4-methoxyphenyl)butan-1-yl]-1H-1,2,3-triazole (270 mg) was foundto be present. yield (quantitatively measured) 25%.

Example 18

[0661] Production of 4-amino-4′-methoxybutyrophenonetrifluoromethanesulfonate

[0662] Trifluoromethanesulfonic acid (4 ml) was ice-cooled, and4-aminobutyric acid (1093 mg, 10.6 mmol) was added. Then, anisole (1 ml,9.25 mmol) was added. The mixture was heated and stirred at 80° C. for50 min. The mixture was cooled to room temperature and added dropwise towater (17 ml) under ice-cooling. The mixture was stirred underice-cooling for 20 min and then at −10° C. for 30 min. The crystals werefiltrated, washed with ice-cooled saturated brine, and dried underreduced pressure to give 4-amino-4′-methoxybutyrophenonetrifluoromethanesulfonate (2.47 g, yield 78%).

[0663]¹H-NMR (D₂O, δ, 300 MHz) 1.88-1.99(2H,m), 2.98(2H,t,J=7.5 Hz),3.09(2H,t,J=7.1 Hz), 3.80(3H,s), 6.95-6.99(2H,m), 7.86-7.91(2H,m).

Example 19

[0664] Production of 1-(4-aminobutyl)-4-methoxybenzene hydrochloride

[0665] 4-Amino-4′-methoxybutyrophenone trifluoromethanesulfonate (60 g,174.8 mmol) was dissolved in tetrahydrofuran/water=1/1 (600 ml) and 10%palladium carbon (water-containing product, 6 g) was added. The mixturewas subjected to catalytic reduction at 50° C. for 7 hours underhydrogen pressure (0.8 Mpa). The catalyst was filtered off and toluene(360 ml) and 2N-potassium hydroxide (180 ml) were added. The mixture waspartitioned and the aqueous layer was extracted with toluene (360 ml).The organic layers were combined and washed with 20% brine (3 times). Tothe residue obtained by concentration under reduced pressure was added2-propanol (300 ml) and con. hydrochloric acid (34 ml) was addeddropwise under ice-cooling. To the residue obtained by concentrationunder reduced pressure was added 2-propanol (300 ml) and the mixture wasconcentrated under reduced pressure. 2-Propanol (300 ml) was added andthe mixture was concentrated under reduced pressure. To the obtainedresidue was added isopropyl ether (200 ml) and the mixture was stirredat room temperature for 10 min. The precipitated crystals were collectedby filtration and dried under reduced pressure to give1-(4-aminobutyl)-4-methoxybenzene hydrochloride (32.1 g, yield 85%).

[0666]¹H-NMR (D₂O, δ, 300 MHz) 1.54-1.57(4H,m), 2.52(2H,t,J=6.5 Hz),2.89(2H,t,J=6.8 Hz), 3.71(3H,s), 6.85-6.88(2H,m), 7.12-7.15(2H,m).

Example 20

[0667] Production of 1-[4-(4-methoxyphenyl)butan-1-yl]-1H-1,2,3-triazole

[0668] 1-(4-Aminobutyl)-4-methoxybenzene hydrochloride (1.0 g, 4.64mmol) was dissolved in water. Toluene (10 ml) and 2N-sodium hydroxide(10 ml) were added and the mixture was partitioned. The organic layerwas washed with 20% brine, dried over anhydrous sodium sulfate andconcentrated under reduced pressure. The residue was dissolved inmethanol (8 ml), and a suspension of 2,2-dichloroacetaldehydetosylhydrazone (2.61 g, 9.28 mmol) in methanol (12 ml) was addeddropwise at 15-20° C. The mixture was stirred at room temperature for 2hours and concentrated under reduced pressure. To the residue was addedethyl acetate (50 ml) and then was added saturated aqueous sodiumhydrogen carbonate (50 ml). The mixture was stirred for 10 min andpartitioned, which was followed by washing with saturated brine andconcentration under reduced pressure. Purification by silica gel columngave 1-[4-(4-methoxyphenyl)butan-1-yl]-1H-1,2,3-triazole (1.1 g, yield100%).

[0669]¹H-NMR (CDCl₃, δ, 300 MHz) 1.57-1.66(2H,m), 1.86-1.97(2H,m),2.58(2H,t,J=7.5 Hz), 3.79(3H,s), 4.37(2H,t,J=7.1 Hz), 6.78-6.83(2H,m),7.01-7.06(2H,m), 7.48(1H,d,J=0.8 Hz), 7.67(1H,d,J=0.8 Hz).

Example 21

[0670] Production of 1-[4-(4-methoxyphenyl)butan-1-yl]-1H-1,2,3-triazole

[0671] 1-(4-Aminobutyl)-4-methoxybenzene hydrochloride (1.0 g, 4.64mmol) was dissolved in water. Toluene (10 ml) and 2N-sodium hydroxide(10 ml) were added and the mixture was partitioned. The organic layerwas washed with 20% brine, dried over anhydrous sodium sulfate andconcentrated under reduced pressure. The residue was dissolved inmethanol (8 ml) and a suspension of 2,2-dichloroacetaldehydetosylhydrazone (2.61 g, 9.28 mmol) in methanol (12 ml) was addeddropwise at 15-20° C. The mixture was stirred at room temperature for 2hours and concentrated under reduced pressure. To the residue was addedtoluene (50 ml) and 2N-sodium hydroxide (50 ml) was added with stirring.The mixture was partitioned 10 min later and quantitatively measured byHPLC. As a result, 1-[4-(4-methoxyphenyl)butan-1-yl]-1H-1,2,3-triazole(417 mg) was found to be present. yield (quantitatively measured) 39%.

Example 22

[0672] Production of 1-[4-(4-methoxyphenyl)butan-1-yl]-1H-1,2,3-triazole

[0673] 1-(4-Aminobutyl)-4-methoxybenzene hydrochloride (1.0 g, 4.64mmol) was dissolved in water. Toluene (10 ml) and 2N-sodium hydroxide(10 ml) were added and the mixture was partitioned. The organic layerwas washed with 20% brine, dried over anhydrous sodium sulfate andconcentrated under reduced pressure. The residue was dissolved inmethanol (8 ml), and a suspension of 2,2-dichloroacetaldehydetosylhydrazone (2.61 g, 9.28 mmol) in methanol (12 ml) was addeddropwise at 15-20° C. After stirring at room temperature for 2 hours,the mixture was concentrated under reduced pressure. To the residue wasadded toluene (50 ml), and 25% aqueous ammonia (50 ml) was added whilestirring the mixture. The mixture was partitioned 10 min later andquantitatively measured by HPLC. As a result,1-[4-(4-methoxyphenyl)butan-1-yl]-1H-1,2,3-triazole (829 mg) was foundto be present. yield (quantitatively measured) 77%.

Example 23

[0674] 1-[4-(4-Methoxyphenyl)butan-1-yl]-1H-1,2,3-triazolemethanesulfonate

[0675] 1-(4-Aminobutyl)-4-methoxybenzene hydrochloride (2.0 g, 9.27mmol) was dissolved in water (10 ml). Toluene (20 ml) and 2N-sodiumhydroxide (10 ml) were added and the mixture was partitioned. Theorganic layer was washed with 20% brine (10 ml) twice, dried overanhydrous sodium sulfate and concentrated under reduced pressure. To theresidue was added methanol (5 ml) and the mixture was concentrated underreduced pressure. The residue was dissolved in methanol (10 ml). Thismethanol solution was added dropwise to a suspension of2,2-dichloroacetaldehyde tosylhydrazone (5213 mg, 18.54 mmol) inmethanol (30 ml) at 20-25° C. The mixture was stirred at roomtemperature for 1 hour 20 min. To the mixture of toluene (20 ml) andsaturated aqueous sodium hydrogen carbonate (60 ml) was added thisreaction mixture, and the mixture was stirred at room temperature for 50min. The organic solvent was evaporated under reduced pressure and theresidue was extracted with toluene (40 ml). 4N-Sodium hydroxide (30 ml)was added, and the mixture was heated to 50-60° C. and partitioned.Water (30 ml) was added, and the mixture was heated to 50-60° C. andpartitioned. Water (30 ml) was added, and the mixture was heated to50-60° C. and partitioned. The organic layer was washed with a mixtureof 20% citric acid (15 ml) and saturated brine (15 ml). After washingwith saturated aqueous sodium hydrogen carbonate (30 ml), it was washedwith water (30 ml) and concentrated under reduced pressure. The residuewas dissolved in ethyl acetate (10 ml) and methanesulfonic acid (0.49ml, 7.55 mmol) was added under ice-cooling. Ethyl acetate (2 ml) wasadded and the mixture was stirred under ice-cooling for 50 min. Theprecipitated crystals were collected by filtration, washed withice-cooled ethyl acetate (8 ml) and dried under reduced pressure to give1-[4-(4-methoxyphenyl)butan-1-yl]-1H-1,2,3-triazole methanesulfonate(2.19 g, yield 72%).

[0676]¹H-NMR (DMSO-d₆, δ, 300 MHz) 1.40-1.51(2H,m), 1.74-1.84(2H,m),2.39(3H,s), 2.51(2H,t,J=7.7 Hz), 3.69(3H,s), 4.38(2H,t,J=7.0 Hz),6.79-6.84(2H,m), 7.04-7.09(2H,m), 7.71(1H,d,J=0.7 Hz), 8.11(1H,d,J=0.7Hz).

Example 24

[0677] 1-[4-(4-Methoxyphenyl)butan-1-yl]-1H-1,2,3-triazole hydrochloride

[0678] 1-(4-Aminobutyl)-4-methoxybenzene hydrochloride (2.0 g, 9.27mmol) was dissolved in water (10 ml). Toluene (20 ml) and 2N-sodiumhydroxide (10 ml) were added and the mixture was partitioned. Themixture was washed 20% brine (10 ml) twice, dried over anhydrous sodiumsulfate and concentrated under reduced pressure. Methanol (5 ml) wasadded and the mixture was concentrated under reduced pressure. Theresidue was dissolved in methanol (10 ml). This methanol solution wasadded dropwise to a slurry of 2,2-dichloroacetaldehyde tosylhydrazone(5213 mg, 18.54 mmol) in methanol (30 ml) at 20-25° C. and the mixturewas stirred at room temperature for 3 hours. The reaction mixture waspoured into a mixture of toluene (19 ml) and saturated aqueous sodiumhydrogen carbonate (57 ml) and the mixture was stirred at roomtemperature for 50 min. The organic solvent was evaporated byconcentration under reduced pressure and the residue was extracted withtoluene (40 ml). 4N-Sodium hydroxide (30 ml) was added, and the mixturewas heated to 50-60° C. and partitioned. Water (30 ml) was added, andthe mixture was heated to 50-60° C. and partitioned. Water (30 ml) wasadded, and the mixture was heated to 50-60° C. and partitioned. Theorganic layer was washed with 20% citric acid (15 ml), and then 3 timeswith water (20 ml), with saturated aqueous sodium hydrogen carbonate (30ml) and with water (30 ml), and concentrated under reduced pressure. Theresidue was dissolved in ethanol (10 ml) and concentrated hydrochloricacid (2.5 ml) was added.

[0679] The mixture was concentrated under reduced pressure and2-propanol was added, and the mixture was concentrated under reducedpressure. Ethyl acetate was added, and the mixture was concentratedunder reduced pressure. Ethyl acetate (10 ml) was added and triturated.The mixture was stirred at room temperature for 40 min. The precipitatedcrystals were collected by filtration and dried under reduced pressureto give 1-[4-(4-methoxyphenyl)butan-1-yl]-1H-1,2,3-triazolehydrochloride (1.61 g, yield 68%).

[0680]¹H-NMR (DMSO-d₆, δ, 300 MHz) 1.39-1.50(2H,m), 1.73-1.83(2H,m)2.49(2H,t,J=7.6 Hz), 3.68(3H,s), 4.37(2H,t,J=7.0 Hz), 6.77-6.83(2H,m),7.02-7.07(2H,m), 7.73(1H,d,J=0.7 Hz), 8.13(1H,d,J=0.7 Hz).

Reference Example 13

[0681] Production of 4-[4-(1H-1,2,3-triazol-1-yl)butyl]phenol

[0682] 1-[4-(4-Methoxyphenyl)butan-1-yl]-1H-1,2,3-triazolemethanesulfonate (4.0 g, 12.22 mmol) was added to 48% hydrobromic acid(8 ml) and the mixture was heated at 80-90° C. for 6 hours. The mixturewas ice-cooled, and after dropwise addition of 4N-sodium hydroxide (32ml), washed with toluene. 6N Hydrochloric acid was added to the aqueouslayer to make pH 6.3. The mixture was extracted with ethyl acetate (30ml) and tetrahydrofuran (15 ml) and washed with water. Active charcoal(200 mg) was added, and the mixture was stirred at room temperature for10 min. The mixture was filtrated and concentrated under reducedpressure. Ethyl acetate (10 ml) was added to the residue, and themixture was refluxed. The mixture was allowed to cool and stirred for 30min, and hexane (10 ml) was added. The mixture was stirred at roomtemperature for 30 min. The precipitated crystals were collected byfiltration and dried under reduced pressure to give4-[4-(1H-1,2,3-triazol-1-yl)butyl]phenol (2.25 g, yield 85%).

[0683]¹H-NMR (CDCl₃-DMSO-d₆, δ, 300 MHz) 1.48-1.59(2H,m),1.80-1.91(2H,m), 2.49(2H,t,J=7.5 Hz), 4.31(2H,t,J=7.2 Hz),6.68-6.73(2H,m), 6.87-6.91(2H,m), 7.45(1H,d,J=0.7 Hz), 7.61(1H,d,J=0.7Hz), 8.12(1H,s).

Reference Example 14

[0684] Production of 4-(trifluoromethyl)cinnamamide

[0685] 4-(Trifluoromethyl)cinnamic acid (64.85 g, 300 mmol) was added intoluene (325 ml) and dimethylformamide (2.2 ml). Thionyl chloride (26.3ml, 361 mmol) was added dropwise at room temperature, and the mixturewas heated at 45° C. for 2 hours. The obtained reaction mixture wasadded dropwise to 25% aqueous ammonia (325 ml) while keeping the mixtureat 5-20° C. The mixture was stirred at room temperature for 1 hour. Theprecipitated crystals were collected by filtration, washed with waterand isopropyl ether and dried under reduced pressure to give4-(trifluoromethyl)cinnamamide (60.76 g, yield 94%).

[0686]¹H-NMR (CDCl₃-DMSO-d₆, δ, 300 MHz) 5.93(1H,s), 6.53(1H,d,J=15.8Hz), 6.75(1H,s), 7.48-7.53(5H,m).

Reference Example 15

[0687] Production of4-(chloromethyl)-2-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]-1,3-oxazole

[0688] 4-(Trifluoromethyl)cinnamamide (1 g, 4.65 mmol) and1,3-dichloroacetone (1.1 g, 8.66 mmol) were added to toluene (5 ml) andthe mixture was refluxed under heating for 8 hours. Ethyl acetate (20ml) was added, and the mixture was washed with water (20 ml) twice andconcentrated under reduced pressure. To the residue was added methanol(4 ml) and the mixture was stirred at room temperature. The crystalswere filtrated and dried under reduced pressure to give4-(chloromethyl)-2-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]-1,3-oxazole(733 mg, yield 55%).

[0689]¹H-NMR (CDCl₃, δ, 300 MHz) 4.56(2H,s), 7.01(1H,d,J=16.4 Hz),7.54-7.68(6H,m).

Reference Example 16

[0690] Production of1-[4-[4-[[2-[(E)-2-(4-trifluoromethyl)phenyl]-ethenyl]-1,3-oxazol-4-yl]methoxy]phenyl]butyl]-1H-1,2,3-triazole

[0691] 4-[4-(1H-1,2,3-Triazol-1-yl)butyl]phenol (400 mg, 1.84 mmol) and4-(chloromethyl)-2-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]-1,3-oxazole(529 mg, 1.84 mmol) were dissolved in dimethylformamide (3 ml),potassium carbonate (279 mg, 2.02 mmol) was added and the mixture wasstirred at 65-75° C. for 4 hours.4-[4-(1H-1,2,3-Triazol-1-yl)butyl]phenol (40 mg, 0.184 mmol) was addedand the mixture was stirred at 65-75° C. for 3 more hours. After coolingto room temperature, water (5 ml) and methanol (3 ml) were added in thisorder, and the mixture was stirred at room temperature for 40 min. Theprecipitated crystals were collected by filtration, washed with waterand dried under reduced pressure to give1-[4-[4-[[2-[(E)-2-(4-trifluoromethylphenyl)ethenyl]-1,3-oxazol-4-yl]methoxy]phenyl]-butyl]-1H-1,2,3-triazole(799 mg, yield 93%).

[0692]¹H-NMR (CDCl₃, δ, 300 MHz) 1.57-1.68(2H,m), 1.88-1.99(2H,m),2.60(2H,t,J=7.5 Hz), 4.39(2H,t,J=7.1 Hz), 5.01(2H,s), 6.89-7.08(5H,m),7.49-7.70(8H,m).

Reference Example 17

[0693] (E)-3-(4-(Trifluoromethyl)phenyl)-2-propenamide

[0694] (E)-3-(4-(Trifluoromethyl)phenyl)-2-propenoic acid (2400 g, 11.1mol) and DMF (N,N-dimethylformamide)(82 ml) were added to toluene (12L). SOCl₂ (52.6 mL, 721 mmol) was added dropwise at room temperature andthe mixture was stirred at 45-50° C. for 1 hour. The toluene solutioncooled to room temperature was added dropwise to 25% aqueous ammonia (12L) at 5-25° C. The mixture was stirred at 45-55° C. for 1 hour. Afterallowing to cool to room temperature and stirring, the mixture wasstirred at the same temperature for 1 hour. The precipitated crystalswere collected by filtration, washed with water (12 L) and dried underreduced pressure to give (E)-3-(4-(trifluoromethyl)phenyl)-2-propenamide(2293 g, 10.7 mol, yield 96%).

[0695]¹H-NMR (DMSO-d₆, δ, 300 MHz) 6.72(1H,d,J=16.1 Hz), 7.20(1H,s)7.46(1H,d,J=15.9 Hz), 7.62(1H,s), 7.67-7.83(4H,m).

Example 25

[0696]4-(Acetoxymethyl)-2-[(E)-2-[4-(trifluoromethyl)phenyl]-ethenyl]-1,3-oxazole

[0697] (E)-3-(4-(Trifluoromethyl)phenyl)-2-propenamide (10.0 g,46.5mmol) and 1,3-dichloroacetone (11.0 g, 86.6 mmol) were added to toluene(50 ml), and the mixture was subjected to refluxing azeotropicdehydration using a Dean-Stark tube for 8.5 hours. The reaction mixturewas concentrated under reduced pressure. To the residue were addeddimethyl sulfoxide (50 ml) and sodium acetate trihydrate (15.8 g, 116.1mmol). The mixture was stirred at 70-75° C. for 4 hours. Methanol (50ml) was added. After allowing to cool to room temperature and stirring,the mixture was stirred under ice-cooling for 1 hour. The precipitatedcrystals were collected by filtration, washed with cold-methanol (30 ml)and dried under reduced pressure to give4-(acetoxymethyl)-2-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]-1,3-oxazole(13.1 g, yield 65%).

[0698]¹H-NMR (CDCl₃, δ, 300 MHz) 2.11(3H,s), 5.13(2H,s),7.00(1H,d,J=16.4 Hz), 7.55(1H,d,J=16.4 Hz), 7.58-7.62(5H,m).

Example 26

[0699]4-(Acetoxymethyl)-2-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]-1,3-oxazole

[0700] (E)-3-(4-(Trifluoromethyl)phenyl)-2-propenamide (950 g, 4.42 mol)and 1,3-dichloroacetone (1045 g, 8.23 mol)were added to toluene (4.75 L)and the mixture was subjected to refluxing azeotropic dehydration usinga Dean-Stark tube for 8 hours. During the reaction, an azeotropicmixture (2.38 L) was removed. The reaction mixture was concentratedunder reduced pressure, and dimethyl sulfoxide (4.75 L) and sodiumacetate (905 g, 11.0 mol) were added to the residue. The mixture wasstirred at 70-80° C. for 3.5 hours. Methanol (4.75 L) was added. Afterallowing to cool to room temperature and stirring, the mixture wasstirred for 1 hour under ice-cooling. The precipitated crystals werecollected by filtration, washed with cold-methanol (1.9 L), and driedunder reduced pressure to give4-(acetoxymethyl)-2-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]-1,3-oxazole(1560 g, yield 51%).

Example 27

[0701][1-[4-[4-[[2-[(E)-2-(4-Trifluoromethyl)phenyl)ethenyl]-1,3-oxazol-4-yl]methoxy]phenyl]butyl]-1H-1,2,3-triazole

[0702]4-(Acetoxymethyl)-2-[(E)-2-[4-(trifluoromethyl)phenyl]-ethenyl]-1,3-oxazole(20.0 g, 64.3 mmol) was dissolved in dimethyl sulfoxide (200 ml), and2N-aqueous sodium hydroxide solution (35 mL, 70.0 mmol) was added at 50°C. The mixture was stirred at about 40° C. for 15 min. Water (200 ml)was added at the same temperature. After allowing to cool to roomtemperature and stirring, the mixture was stirred at the sametemperature for 1 hour. The precipitated crystals were collected byfiltration, washed with (60 ml) and dried under reduced pressure to give4-(hydroxymethyl)-2-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]-1,3-oxazole(16.4 g, 61.1 mmol, yield 95%).

[0703] The obtained4-(hydroxymethyl)-2-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]-1,3-oxazole(1.00 g, 3.71 mmol) and diisopropylethylamine (0.95 mL, 5.44 mmol) wereadded to THF (tetrahydrofuran) (15 ml). Methanesulfonyl chloride (0.45mL, 5.81 mmol) was added dropwise under ice-cooling. The mixture wasstirred at the same temperature for 1 hour.4-[4-(1H-1,2,3-Triazol-1-yl)butyl]phenol (900 mg, 4.14 mmol) andtetra(n-butyl)ammonium bromide (60 mg, 0.19 mmol) were added at the sametemperature. A 2N aqueous sodium hydroxide solution (7.5 mL, 15.0 mmol)was added dropwise at not more than 15° C. and the mixture was stirredwith reflux for 1 hour. After allowing to cool to room temperature andstirring, the organic layer was concentrated under reduced pressure.Ethanol (20 ml) was added to the residue, and the mixture was stirredwith reflux. Water (20 ml) was added dropwise at the same temperature.After allowing to cool to room temperature and stirring, the mixture wasice-cooled. The precipitated crystals were collected by filtration,washed with water (20 ml) and dried under reduced pressure to give[1-[4-[4-[[2-[(E)-2-(4-trifluoromethylphenyl)ethenyl]-1,3-oxazol-4-yl]methoxy]phenyl]butyl]-1H-1,2,3-triazole(1.61 g, 3.44 mmol, yield 88%).

[0704]¹H-NMR (CDCl₃, δ, 300 MHz) 1.57-1.68(2H,m), 1.88-1.99(2H,m),2.60(2H,t,J=7.5 Hz), 4.39(2H,t,J=7.1 Hz), 5.01(2H,s), 6.89-7.08(5H,m),7.49-7.70(8H,m).

Example 28

[0705][1-[4-[4-[[2-[(E)-2-(4-Trifluoromethyl)phenyl)ethenyl]-1,3-oxazol-4-yl]methoxy]phenyl]butyl]-1H-1,2,3-triazole

[0706]4-(Acetoxymethyl)-2-[(E)-2-[4-(trifluoromethyl)phenyl]-ethenyl]-1,3-oxazole(1556 g, 2.23 mol), 2N-aqueous sodium hydroxide solution (2.4 L, 4.8mol) and activated carbon (47 g) were added to methanol (4.7 L), and themixture was refluxed under stirring for 1 hour. The activated carbon andthe insoluble material were removed by filtration under pressurization.The residue was washed with methanol/water (2:1) (470 ml). The washingsolution was combined with the filtrate and the mixture was refluxed.Water (3.3 L) was added at the same temperature. After allowing to coolto room temperature and stirring, the mixture was stirred at the sametemperature for 1 hour. The precipitated crystals were collected byfiltration, washed with water (4.7 L) and dried under reduced pressureto give4-(hydroxymethyl)-2-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]-1,3-oxazole(568.5 g, 2.11 mol, yield 95%).

[0707] The obtained4-(hydroxymethyl)-2-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]-1,3-oxazole(567 g, 2.11 mol) and diisopropylethylamine (340 g, 2.63 mol) were addedto THF (3.4 L). A solution of methanesulfonyl chloride (302 g, 2.63 mol)in THF (567 ml) was added dropwise under ice-cooling. The mixture wasstirred at the same temperature for 1 hour and diisopropylethylamine(27.3 g, 0.21 mol), methanesulfonyl chloride (24.2 g, 0.21 mol) and THF(57 ml) solution were added. The mixture was stirred under reflux for1.5 hours. After allowing to cool to room temperature, 15% aqueoussodium hydroxide (1.96 kg, 7.35 mol) was added dropwise.4-[4-(1H-1,2,3-Triazol-1-yl)butyl]phenol (503 g, 2.32 mol) andtetra(n-butyl)ammonium bromide (68.0 g,0.21 mol) were added at the sametemperature, and the mixture was refluxed for 4 hours under stirring.Water (3.1 L) and methanol (7.4 L) were added dropwise at the sametemperature. After allowing to cool to room temperature, the mixture wasstirred at the same temperature for 1 hour. The precipitated crystalswere collected by filtration, washed with THF/methanol/water (1:1:2)(2.8 L), water (2.8 L) and cold-methanol (2.8 L) and dried under reducedpressure to give[1-[4-[4-[[2-[(E)-2-(4-trifluoromethylphenyl)ethenyl]-1,3-oxazol-4-yl]methoxy]phenyl]-butyl]-1H-1,2,3-triazole(883 g, 1.88 mol, yield 85%).

Reference Example 18

[0708]4-(Hydroxymethyl)-2-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]-1,3-oxazole

[0709] (E)-3-(4-(Trifluoromethyl)phenyl)-2-propenamide (20.0 g, 92.9mmol) was added to toluene (75 ml), and 1,3-dichloroacetone (22.0 g,173.3 mmol) and toluene (25 ml) were added. The mixture was subjected torefluxing azeotropic dehydration for 9 hours. The reaction mixture wasdivided into two equal portions and one of them was concentrated underreduced pressure. To the residue were added dimethyl sulfoxide (100 ml),sodium acetate trihydrate (15.9 g, 116.8 mmol) and water (20 ml). Themixture was stirred at 70-75° C. for 4.5 hours. 2N-Aqueous sodiumhydroxide solution (60 ml) was added at the same temperature and themixture was stirred for 1 hour. After allowing to cool to roomtemperature, toluene (400 ml) and water (400 ml) were added and themixture was partitioned. After washing with 5% brine (200 ml), theorganic layer was concentrated under reduced pressure. To the residuewas added methanol (10 ml) and the mixture was heated to 60° C. to allowdissolution. After allowing to cool to room temperature and stirring,the mixture was stirred for 1 hour under ice-cooling. The precipitatedcrystals were collected by filtration, washed with cold-methanol (5 ml)and dried under reduced pressure to give4-(hydroxymethyl)-2-[(E)-2-[4-(trifluoromethyl)phenyl]-ethenyl]-1,3-oxazole(5.96 g, 22.1 mmol, yield 48%).

[0710]¹H-NMR (CDCl₃, δ, 300 MHz) 2.83(1H,s), 4.69(2H,d,J=5.2 Hz),6.96(1H,d,J=13.1 Hz), 7.51(1H,d,J=12.7 Hz), 7.55-7.66(5H,m).

Reference Example 19

[0711]4-(Hydroxymethyl)-2-[(E)-2-[4-(trifluoromethyl)phenyl]-ethenyl]-1,3-oxazole

[0712] (E)-3-(4-(Trifluoromethyl)phenyl)-2-propenamide (4.30 g, 20.0mmol) and 1,3-dichloroacetone (4.75 g, 37.4 mmol) were added to toluene(20 ml) and the mixture was subjected to refluxing azeotropicdehydration using a Dean-Stark tube for 6 hours. The reaction mixturewas allowed to cool to room temperature, and DMF (50 ml), water (30 ml)and potassium carbonate (13.7 g, 99.1 mmol) were added. The mixture wasstirred at 100° C. for 1.5 hours. After allowing to cool to roomtemperature, ethyl acetate (200 ml) and water (150 ml) were added andthe mixture was partitioned. The organic layer was washed withwater/saturated brine (1:1, 100 ml). To the organic layer was addedethyl acetate (400 ml), and the mixture was washed with water (200 ml)twice and concentrated under reduced pressure. Ethanol (30 ml) was addedto the residue. Water (38 ml) was added and the precipitated crystalswere collected by filtration, washed with water (40 ml) and dried underreduced pressure to give4-(hydroxymethyl)-2-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]-1,3-oxazole(3.3 g, 3.71 mmol, yield 62%).

Referenc Example 20

[0713][2-[(E)-2-[4-(Trifluoromethyl)phenyl]ethenyl]-1,3-oxazol-4-yl]methylmethanesulfonate

[0714]4-(Hydroxymethyl)-2-[(E)-2-[4-(trifluoromethyl)phenyl]-ethenyl]-1,3-oxazole(5.0 g, 18.6 mmol) and triethylamine (3.1 mL, 22.4 mmol) were added toTHF solution (25 ml), and methanesulfonyl chloride (1.8 mL, 23.3 mmol)was added dropwise under ice-cooling. THF (25 ml) was added at the sametemperature and the mixture was stirred for 40 min. The mixture wasstirred at room temperature for 1 more hour. To the mixture was addedwater (25 ml) and the mixture was extracted with ethyl acetate (25 ml).The organic layer was washed with water (25 ml). The aqueous layers werecombined and extracted with ethyl acetate (25 ml). The organic layerswere combined and concentrated. Ethyl acetate (40 ml) and isopropylether (10 ml) were added to the residue. The mixture was heated to 60°C. for dissolution. After allowing to cool to room temperature withstirring, isopropyl ether (10 ml) was added under ice-cooling and theprecipitated crystals were collected by filtration. The crystals werewashed with isopropyl ether (10 ml) and dried under reduced pressure togive[2-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]-1,3-oxazol-4-yl]methylmethanesulfonate(5.1 g, 14.5 mmol, yield 78%).

[0715]¹H-NMR (CDCl₃, δ, 300 MHz) 3.09(3H,s), 5.22(1H,s),7.00(1H,d,J=16.4 Hz), 7.57(1H,d,J=16.4 Hz), 7.60-7.69(4H,m), 7.78(1H,s).

Refer nce Exampl 21

[0716][1-[4-[4-[[2-[(E)-2-(4-Trifluoromethyl)phenyl)ethenyl]-1,3-oxazol-4-yl]methoxy]phenyl]butyl]-1H-1,2,3-triazole

[0717][2-[(E)-2-[4-(Trifluoromethyl)phenyl]ethenyl]-1,3-oxazol-4-yl]methylmethanesulfonate(500 mg, 1.44 mmol), 4-[4-(1H-1,2,3-triazol-1-yl)butyl]phenol (344 mg,1.58 mmol) and tetra(n-butyl)ammonium bromide (45 mg, 0.14 mmol) wereadded to THF (5 ml), and 1N-aqueous sodium hydroxide solution (3.0 mL,3.00 mmol) was added. The mixture was stirred at room temperature for 5hours. 10% Brine (10 ml) was added and the mixture was extracted withethyl acetate (10 ml). The organic layer was washed with 10% brine (10ml). The aqueous layers were combined and extracted with ethyl acetate(10 ml). The organic layers were combined and concentrated. Ethanol (15ml) was added to the residue and the mixture was refluxed under heatingfor dissolution. After allowing to cool to room temperature andstirring, the mixture was stirred for 1 hour under ice-cooling. Theprecipitated crystals were collected by filtration, washed withcold-ethanol (2 ml) and dried under reduced pressure to give[1-[4-[4-[[2-[(E)-2-(4-trifluoromethylphenyl)ethenyl]-1,3-oxazol-4-yl]methoxy]phenyl]butyl]-1H-1,2,3-triazole(556 mg, 1.19 mmol, yield 81%).

Example 29

[0718][1-[4-[4-[[2-[(E)-2-(4-Trifluoromethyl)phenyl)ethenyl]-1,3-oxazol-4-yl]methoxy]phenyl]butyl]-1H-1,2,3-triazole

[0719] (E)-3-(4-(Trifluoromethyl)phenyl)-2-propenamide (4.00 g, 18.59mmol) and 1,3-dichloroacetone (3.54 g, 27.89 mmol) were added to toluene(14 ml) and the mixture was subjected to refluxing azeotropicdehydration using a Dean-Stark tube for 3 hours. A solution of sulfuricacid (91 mg) in toluene (1 ml) was added at the same temperature and themixture was further subjected to refluxing azeotropic dehydration for3.5 hours. The reaction mixture was concentrated under reduced pressure,and THF (20 ml) and tetra(n-butyl)ammonium bromide (428 mg, 1.328 mmol)were added to the residue. 30% Aqueous potassium hydroxide solution(12.42 g, 66.4 mmol) was added dropwise at 20-30° C. and the mixture wasstirred at the same temperature for 15 min.4-[4-(1H-1,2,3-Triazol-1-yl)butyl]phenol (2.89 g, 13.28 mmol) was addedand the mixture was refluxed under stirring for 2 hours. Water (13.4 ml)and methanol (20 ml) were added dropwise at the same temperature. Afterallowing to cool to room temperature and stirring, the mixture wasstirred at the same temperature for 1 hour. The precipitated crystalswere collected by filtration, washed with cold-methanol (40 ml) anddried under reduced pressure to give[1-[4-[4-[[2-[(E)-2-(4-trifluoromethylphenyl)ethenyl]-1,3-oxazol-4-yl]methoxy]phenyl]butyl]-1H-1,2,3-triazole(5.35 g,11.42 mmol, yield 86%).

Reference Example 22

[0720] Production of1-[4-[4-[[2-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]-1,3-oxazol-4-yl]methoxy]phenyl]butyl]-1H-1,2,3-triazole

[0721]1-[4-[4-[[2-[(E)-2-[4-(Trifluoromethyl)phenyl]ethenyl]-1,3-oxazol-4-yl]methoxy]phenyl]butyl]-1H-1,2,3-triazole(5.0 g) was added to water/1-propanol=1/9 (65 ml), and active charcoal(100 mg) was added. After refluxing under heating, an insoluble materialwas filtered off while hot, and the residue was washed withwater/1-propanol=1/9 (5 ml). The filtrate was refluxed again and wasallowed to cool and stirred at 50° C. to 55° C. for 30 min. Water (56ml) was added dropwise at the same temperature and the mixture wasstirred at from 50° C. to 60° C. for 20 hours. The crystals werefiltrated, washed with water (50° C.) and dried under reduced pressureat 40° C. to give1-[4-[4-[[2-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]-1,3-oxazol-4-yl]methoxy]-phenyl]butyl]-1H-1,2,3-triazole(4.29 g, yield 92%) as crystals (the same crystals as those obtained inExample 4 of Japanese Patent Application No. 2000-108204).

[0722] The crystals were analyzed by powder X ray diffraction, theresults of which are shown in the following.

[0723] The crystals showed a powder X ray diffraction pattern showingcharacteristic peaks at diffraction angles (2θ) of powder X raydiffraction of 15.88, 21.22 and 21.82 degrees. The powder X raydiffraction chart is shown in FIG. 1.

Example 30

[0724] Production of1-[4-[4-[[2-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]-1,3-oxazol-4-yl]methoxy]phenyl]butyl]-1H-1,2,3-triazole

[0725]1-[4-[4-[[2-[(E)-2-[4-(Trifluoromethyl)phenyl]ethenyl]-1,3-oxazol-4-yl]methoxy]phenyl]butyl]-1H-1,2,3-triazole(150.0 g) was added to acetone (1.5 L). The mixture was refluxed underheating and the insoluble material was filtered off. The residue waswashed with acetone (60 ml) and the filtrate and the washing solutionwere refluxed. Water (150 ml) was added dropwise under reflux. Themixture was allowed to cool and stirred at 30° C. Water (390 ml) wasadded dropwise and the mixture was stirred at room temperature for 2hours and under ice-cooling for 5.5 hours. The reaction mixture wasfiltrated, washed with ice-cooled acetone/water=1/1 (300 ml×2) and driedunder reduced pressure at 40° C. to give1-[4-[4-[[2-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]-1,3-oxazol-4-yl]methoxy]-phenyl]butyl]-1H-1,2,3-triazoleas crystals (141.4 g, yield 94%).

[0726] The crystals were analyzed by powder X ray diffraction, theresults of which are shown in the following.

[0727] The crystals showed a powder X ray diffraction pattern showingcharacteristic peaks at diffraction angles (2θ) of powder X raydiffraction of 6.98, 14.02, 17.56, 21.10 and 24.70 degrees. The powder Xray diffraction chart is shown in FIG. 2.

Reference Example 23

[0728] Production of1-[4-[4-[[2-[(E)-2-[4-(trifluoromethyl)phenyl]-ethenyl]-1,3-oxazol-4-yl]methoxy]phenyl]butyl]-1H-1,2,3-triazolemethanesulfonate

[0729]1-[4-[4-[[2-[(E)-2-[4-(Trifluoromethyl)phenyl]ethenyl]-1,3-oxazol-4-yl]methoxy]phenyl]butyl]-1H-1,2,3-triazole(1.0 g) was dissolved in ethyl acetate (50 ml) and tetrahydrofuran (5ml). A solution of methanesulfonic acid (205 mg) in tetrahydrofuran (5ml) was added dropwise. The crystals were precipitated. The mixture wasstirred at room temperature for 20 min and under ice-cooling for 50 min.The reaction mixture was concentrated under reduced pressure until theliquid amount became about half. After stirring the mixture underice-cooling for 30 min, the mixture was filtrated, washed with ethylacetate/isopropyl ether=1/1 (3 ml) and dried under reduced pressure (40°C.) to give1-[4-[4-[[2-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]-1,3-oxazol-4-yl]methoxy]phenyl]butyl]-1H-1,2,3-triazolemethanesulfonate (1.18 g, yield 98%).

[0730]¹H-NMR (300 MHz, CDCl₃, δ) 1.61-1.69(2H,m), 1.94-2.05(2H,m),2.62(2H,t,J=7.35 Hz),2.90(3H,s),4.51(2H,t,J=7.14 Hz)5.05(2H,s),6.91-7.13(5H,m),7.60-7.74(6H,m),7.97(1H,s),8.16(1H,s).

Reference Example 24

[0731] Production of1-[4-[4-[[2-[(E)-2-[4-(trifluoromethyl)phenyl]-ethenyl]-1,3-oxazol-4-yl]methoxy]phenyl]butyl]-1H-1,2,3-triazolep-toluenesulfonate

[0732]1-[4-[4-[[2-[(E)-2-[4-(Trifluoromethyl)phenyl]ethenyl]-1,3-oxazol-4-yl]methoxy]phenyl]butyl]-1H-1,2,3-triazole(1.0 g) was dissolved in ethyl acetate (50 ml) and tetrahydrofuran (5ml). A solution of p-toluenesulfonic acid monohydrate (406 mg) intetrahydrofuran (5 ml) was added dropwise. The crystals wereprecipitated. The mixture was stirred at room temperature for 2 hours 20min and filtrated. The mixture was washed with ethyl acetate/isopropylether=1/1 (3 ml) and dried under reduced pressure (40° C.) to give1-[4-[4-[[2-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]-1,3-oxazol-4-yl]methoxy]phenyl]butyl]-1H-1,2,3-triazolep-toluenesulfonate (1.1 g, yield 80%).

[0733]¹H-NMR (300 MHz, CDCl₃, δ) 1.58-1.66(2H,m),1.90-2.01(2H,m),2.31(3H,s), 2.59(2H,t,J=7.28 Hz), 4.49(2H,t,J=7.06 Hz),5.05(2H, s),6.88-7.19(7H,m), 7.61-7.81(8H,m), 8.02(1H,s), 8.16(1H,s).

Reference Example 25

[0734] Production of1-[4-[4-[[2-[(E)-2-[4-(trifluoromethyl)phenyl]-thenyl]-1,3-oxazol-4-yl]methoxy]phenyl]butyl]-1H-1,2,3-triazolebenzenesulfonate

[0735]1-[4-[4-[[2-[(E)-2-[4-(Trifluoromethyl)phenyl]ethenyl]-1,3-oxazol-4-yl]methoxy]phenyl]butyl]-1H-1,2,3-triazole(1.0 g) was dissolved in ethyl acetate (50 ml) and tetrahydrofuran (5ml). A solution of benzenesulfonic acid monohydrate (376 mg) intetrahydrofuran (5 ml) was added dropwise. The crystals wereprecipitated. The mixture was stirred room temperature for 2 hours andfiltrated. The mixture was washed with ethyl acetate/isopropyl ether=1/1(3 ml) and dried under reduced pressure (40° C.) to give1-[4-[4-[[2-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]-1,3-oxazol-4-yl]methoxy]phenyl]butyl]-1H-1,2,3-triazolebenzenesulfonate (1.05 g, yield 78%).

[0736]¹H-HNR (300 MHz, CDCl₃+DMSO-d₆, δ) 1.54-1.66(2H,m),1.88-1.99(2H,m), 2.58(2H,t,J=7.47 Hz), 4.44(2H,t,J=7.17 Hz),5.00(2H,s),6.87-7.06(5H,m), 7.39-7.44(3H,m),7.53-7.70(6H,m), 7.80(1H,s),7.87-7.91(2H,m),7.99(1H,s).

Reference Example 26

[0737] Production of1-[4-[4-[[2-[(E)-2-[4-(trifluoromethyl)phenyl]-ethenyl]-1,3-oxazol-4-yl]methoxy]phenyl]butyl]-1H-1,2,3-triazolesulfate

[0738]1-[4-[4-[[2-[(E)-2-[4-(Trifluoromethyl)phenyl]ethenyl]-1,3-oxazol-4-yl]methoxy]phenyl]butyl]-1H-1,2,3-triazole(1.0 g) was dissolved in ethyl acetate (50 ml) and tetrahydrofuran (5ml). A solution of sulfuric acid (209 mg) in tetrahydrofuran (5 ml) wasadded dropwise. The crystals were precipitated. The mixture was stirredat room temperature for 40 min and filtrated. The mixture was washedwith ethyl acetate (3 ml) and dried under reduced pressure (40° C.) togive1-[4-[4-[[2-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]-1,3-oxazol-4-yl]methoxy]-phenyl]butyl]-1H-1,2,3-triazolesulfate (1.13 g, yield 93%).

[0739]¹H-HNR (300 MHz, CDCl₃+DMSO-d₆, δ) 1.56-1.66(2H,m),1.89-2.00(2H,m), 2.60(2H,t,J=7.50 Hz), 4.45(2H,t,J=7.11 Hz), 5.00(2H,s), 6.88-7.10(5H,m), 7.53-7.70(5H,m), 7.93(1H,s), 7.82(1H,s),7.85(1H,s).

Reference Example 27

[0740] Production of1-[4-[4-[[2-[(E)-2-[4-(trifluoromethyl)phenyl]-ethenyl]-1,3-oxazol-4-yl]methoxy]phenyl]butyl]-1H-1,2,3-triazolehydrochloride

[0741]1-[4-[4-[[2-[(E)-2-[4-(Trifluoromethyl)phenyl]ethenyl]-1,3-oxazol-4-yl]methoxy]phenyl]butyl]-1H-1,2,3-triazole(1.5g) was dissolved in tetrahydrofuran (75 ml). Concentrated hydrochloricacid (0.3 ml) was added dropwise. The crystals were precipitated. Themixture was stirred at room temperature for 40 min and filtrated. Themixture was washed with ethyl acetate (3 ml) and dried under reducedpressure (40° C.) to give1-[4-[4-[[2-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]-1,3-oxazol-4-yl]methoxy]phenyl]butyl]-1H-1,2,3-triazolehydrochloride(1.09 g, yield 67%).

[0742]¹H-HNR (300 MHz, CDCl₃+DMSO-d₆, δ) 1.60-1.66(2H,m),1.93-1.98(2H,m), 2.61(2H,t,J=7.53 Hz), 4.43(2H,t,J=7.08 Hz), 5.03(2H,s),6.90-7.09(5H,m), 7.55-7.81(8H,m).

INDUSTRIAL APPLICABILITY

[0743] According to the production methods of the present invention,1-substituted-1,2,3-triazole compounds having a tyrosine kinase(especially HER2) inhibitory action can be produced efficiently in ahigh yield at an industrial large scale by a convenient method.

What is claimed is:
 1. A method for producing a compound of the formula:

wherein R^(a1) and R^(a2) are each a hydrogen atom, a substitutedhydroxy, a substituted thiol, a substituted amino, an optionallysubstituted hydrocarbon group, an optionally substituted heterocyclicgroup or an acyl; R^(a3) is a group of the formula:

wherein R^(a4) and R^(a5) are each a hydrogen atom, an optionallysubstituted hydroxy, an optionally substituted thiol, an optionallysubstituted amino, an optionally substituted hydrocarbon group, anoptionally substituted heterocyclic group or an acyl, or R^(a4) andR^(a5) in combination form oxo, R^(a6) is an optionally substitutedaromatic group, and m^(a) is an integer of 0 to 10; or p1 two or threefrom R^(a1), R^(a2) and R^(a3) form an optionally substituted ring,together with the adjacent carbon atom; and R^(a7) and R^(a8) are each ahydrogen atom, a halogen, an optionally substituted hydroxy, anoptionally substituted thiol, an optionally substituted amino, anoptionally substituted hydrocarbon group, an optionally substitutedheterocyclic group or an acyl, which method comprises reacting acompound of the formula:

wherein X^(a) is a leaving group and other symbols are as defined above,or a salt thereof, and a compound of the formula:

wherein each symbol is as defined above, or a salt thereof, (1) in asecondary or tertiary alcohol in the presence of a base, or (2) in theabsence of a base.
 2. The production method of claim 1, which comprisesreaction in a secondary or tertiary alcohol in the presence of a base.3. The production method of the claim 1, which comprises reaction in atertiary alcohol in the presence of a base.
 4. The production method ofclaim 1, wherein R^(a1) is a hydrogen atom.
 5. The production method ofcliam 1, wherein R^(a1) and R^(a2) are each a hydrogen atom.
 6. Theproduction method of claim 1 above, wherein R^(a3) is a group of theformula:

wherein each symbol is as defined in claim
 1. 7. The production methodof claim 6, wherein R^(a4) and R^(a5) are each a hydrogen atom.
 8. Theproduction method of claim 6, wherein R^(a6) is an optionallysubstituted phenyl.
 9. The production method of claim 6, wherein m^(a)is
 3. 10. The production method of claim 1, wherein R^(a7) and R^(a8)are each a hydrogen atom.
 11. A salt of a compound of the formula:


12. A compound of the formula:

wherein X^(a′) is a halogen atom, OSO₂R^(a) or OCOR^(a) wherein R^(a) isan optionally substituted hydrocarbon group.
 13. A method for producinga compound of the formula:

wherein X^(a′) is a halogen atom, OSO₂R^(a) or OCOR^(a) wherein R^(a) isan optionally substituted hydrocarbon group, which comprises reacting acompound of the formula:

wherein M^(a) is a hydrogen atom, an alkali metal atom or an alkalineearth metal atom, and 1) thionyl halide, 2) oxalyl halide, 3) a compoundof the formula: R^(a)SO₂X^(a) or (R^(a)SO₂)₂O wherein R^(a) is asdefined above and X^(a) is a leaving group, or 4) a compound of theformula: R^(a)COX^(a) or (R^(a)CO)₂O wherein R^(a) and X^(a) are asdefined above, under basic conditions.
 14. A compound of the formula:

or a salt thereof.
 15. The production method of claim 1, wherein R^(a1),R^(a2), R^(a7) and R^(a8) are each a hydrogen atom and R^(a3) is3-[4-(t-butoxyphenyl)]propyl.
 16. A method for producing a compound ofthe formula:

which comprises reacting a compound of the formula:

wherein M^(a) is a hydrogen atom, an alkaline metal atom or an alkalineearth metal atom, and 1) thionyl halide, 2) oxalyl halide, 3) a compoundof the formula: R^(a)SO₂X^(a) or (R^(a)SO₂)₂O wherein R^(a) is anoptionally substituted hydrocarbon group and X^(a) is a leaving group or4) a compound of the formula: R^(a)COX^(a) or (R^(a)CO)₂O wherein R^(a)and X^(a) are as defined above, under basic conditions to give acompound of the formula:

wherein X^(a′) is a halogen atom, OSO₂R^(a) or OCOR^(a) wherein R^(a) isas defined above, and reacting this compound with a compound of theformula:

or a salt thereof, (1) in the presence of a base in a secondary ortertiary alcohol, or (2) in the absence of a base to give a compound ofthe formula:

and deprotecting this compound.
 17. A method for producing a compound ofthe formula:

which comprises deprotecting a compound of the formula:


18. A method for producing a compound of the formula:

which comprises deprotecting a compound of the formula:


19. A method for producing a compound of the formula:

wherein R^(b1), R^(b2) and R^(b3) are each a hydrogen atom, anoptionally substituted hydroxy, an optionally substituted thiol, anoptionally substituted amino, an optionally substituted hydrocarbongroup, an optionally substituted heterocyclic group or an acyl, or twoor three from R^(b1), R^(b2) and R^(b3) form, together with the adjacentcarbon atom, an optionally substituted ring, and R^(b4) and R^(b5) areeach a hydrogen atom, an optionally substituted hydroxy, an optionallysubstituted thiol, an optionally substituted amino, an optionallysubstituted hydrocarbon group, an optionally substituted heterocyclicgroup or an acyl, and R^(b6) is an optionally substituted alkyl or anoptionally substituted phenyl, or a salt thereof, which comprisesreacting a compound of the formula:

wherein each symbol is as defined above, or a salt thereof and acompound of the formula:

wherein X^(b1) and X^(b2) are each a halogen, and R^(b4), R^(b5) andR^(b6) are as defined above, or a salt thereof, and treating thereaction mixture with a base.
 20. The production method of claim 19,wherein R^(b1) is a hydrogen atom.
 21. The production method of claim19, wherein R^(b1) and R^(b2) are each a hydrogen atom.
 22. Theproduction method of claim 19, wherein R^(b3) is a group of the formula:

wherein R^(b7) and R^(b8) are each a hydrogen atom, an optionallysubstituted hydroxy, an optionally substituted thiol, an optionallysubstituted amino, an optionally substituted hydrocarbon group, anoptionally substituted heterocyclic group or an acyl, or R^(b7) andR^(b8) in combination form oxo, R^(b9) is an optionally substitutedaromatic group, and m^(b) is an integer of 0 to
 10. 23. The productionmethod of claim 22, wherein R^(b7) and R^(b8) are each a hydrogen atom,R^(b9) is an optionally substituted phenyl, and m^(b) is
 3. 24. Theproduction method of claim 23, wherein R^(b1) and R^(b2) are each ahydrogen atom.
 25. The production method of claim 19, wherein R^(b4) andR^(b5) are each a hydrogen atom.
 26. The production method of claim 19,wherein R^(b6) is a phenyl substituted by alkyl.
 27. A method forproducing a compound of the formula:

wherein, R^(b10) is an optionally substituted amino, an optionallysubstituted hydrocarbon group, an optionally substituted heterocyclicgroup or an acyl, R^(b11) is a substituent, n^(b) is an integer of 0 to4, and R^(b12) is an optionally substituted alkylene, an optionallysubstituted alkenylene or an optionally substituted alkynylene, or asalt thereof, which comprises reacting a compound of the formula:

wherein each symbol is as defined above, or a salt thereof and acompound of the formula: HOOC—R^(b12)—NH₂ wherein R^(b12) is as definedabove, a salt thereof or a reactive derivative thereof.
 28. A method forproducing a compound of the formula:

wherein each symbol is as defined in claim 27, or a salt thereof, whichcomprises reacting a compound of the formula

wherein each symbol is as defined above, or a salt thereof, and acompound of the formula HOOC—R^(b12)—NH₂ wherein R^(b12) is as definedabove, or a salt thereof or a reactive derivative thereof, and reducingthe resulting compound of the formula

wherein each symbol is as defined above, or a salt thereof.
 29. A methodfor producing a compound of the formula:

wherein each symbol is as defined in claim 27, or a salt thereof, whichcomprises reacting a compound of the formula

wherein each symbol is as defined above, or a salt thereof, and acompound of the formula HOOC—R^(b12)—NH₂ wherein R^(b12) is as definedabove, a salt thereof or a reactive derivative thereof, reducing theresulting compound of the formula

wherein each symbol is as defined above, or a salt thereof, reacting theresulting compound of the formula

wherein each symbol is as defined above, or a salt thereof with acompound of the formula

wherein each symbol is as defined in claim 19, or a salt thereof, andtreating the reaction mixture with a base.
 30. The production method ofclaim 29, wherein R^(b4) and R^(b5) are each a hydrogen atom, R^(b10) isa C₁₋₃ alkyl, R^(b12) is a trimethylene and n^(b) is
 0. 31. Atrifluoromethanesulfonate of a compound of the formula:

wherein R^(b12′) is trimethylene and other symbols are as defined inclaim
 27. 32. A method for producing a compound of the formula:

wherein Ar^(c) is an optionally substituted aromatic group, R^(c1) andR^(c2) are each a hydrogen atom or a lower alkyl, R^(c3) and R^(c4) areeach a hydrogen atom or a lower alkyl, Y^(c) is C, S or SO and R^(c5) isa hydrogen atom, a lower alkyl, an optionally substituted phenyl, anoptionally substituted benzyloxy or an optionally substitutedbenzylamino, or a salt thereof, which comprises reacting a reactionmixture of a compound of the formula:

wherein each symbol is as defined above, or a salt thereof and acompound of the formula:

wherein X^(c1) and X^(c2) are each a halogen, and other symbols are asdefined above, or a salt thereof, with a compound of the formula:

wherein M^(c) is a hydrogen atom or a metal, and other symbols are asdefined above, or a salt thereof.
 33. The production method of claim 32,wherein Ar^(c) is 4-trifluoromethylphenyl.
 34. The production method ofclaim 32, wherein R^(c1), R^(c2), R^(c3) and R^(c4) are each a hydrogenatom and R^(c5) is methyl.
 35. The compound of the formula

wherein each symbol is as defined in claim 32, or a salt thereof.
 36. Amethod for producing a compound of the formula:

wherein each symbol is as defined in claim 32, or a salt thereof, whichcomprises subjecting a compound of the formula

wherein each symbol is as defined above, or a salt thereof to hydrolysisor catalytic reduction, subjecting the obtained compound of the formula:

wherein each symbol is as defined above, or a salt thereof tosulfonylation or halogenation, and reacting the compound with a compoundof the formula:

wherein n^(c) is an integer of 1 to 10, or a salt thereof.
 37. Theproduction method of claim 36, wherein Ar^(c) is4-trifluoromethylphenyl.
 38. The production method of claim 36, whereinR^(c1), R^(c2), R^(c3) and R^(c4) are each a hydrogen atom, R^(c5) ismethyl and n^(c) is
 4. 39. A method for producing a compound of theformula

wherein each symbol is as defined in claim 32, or a salt thereof, whichcomprises reacting a reaction mixture of a compound of the formula:

wherein each symbol is as defined above, or a salt thereof and acompound of the formula:

wherein R^(c3) and R^(c4) are as defined above and X^(c1) and X^(c2) areas defined in claim 32, or a salt thereof, with a compound of theformula:

wherein each symbol is as defined in claim 32, or a salt thereof,subjecting the resulting compound to hydrolysis or catalytic reduction,and reacting the obtained compound with a compound of the formula:

wherein n^(c) is as defined above, or a salt thereof.
 40. The productionmethod of claim 39, wherein Ar^(c) is 4-trifluoromethylphenyl.
 41. Theproduction method of claim 39, wherein R^(c1), R^(c2), R^(c3) and R^(c4)are each a hydrogen atom, R^(c5) is methyl and n^(c) is
 4. 42. A methodfor producing a compound of the formula:

wherein n^(c) is an integer of 1 to 10 and other symbols are as definedin claim 32, or a salt thereof, which comprises subjecting a reactionmixture of a compound of the formula:

wherein each symbol is as defined above, or a salt thereof and acompound of the formula

wherein R^(c3) and R^(c4) are as defined above and X^(c1) and X^(c2) areas defined in claim 32, or a salt thereof, to hydrolysis, subjecting theresulting compound of the formula

wherein each symbol is as defined above, or a salt thereof tosulfonylation or halogenation, and reacting the resulting compound witha compound of the formula

wherein n^(c) is as defined above, or a salt thereof.
 43. A method forproducing a compound of the formula

wherein n^(c) is an integer of 1 to 10 and other symbols are as definedin claim 32, or a salt thereof, which comprises reacting a reactionmixture of a compound of the formula

wherein each symbol is as defined above, or a salt thereof and acompound of the formula:

wherein R^(c3) and R^(c4) are as defined above and X^(c1) and X^(c2) areas defined in claim 32, or a salt thereof, with a compound of theformula:

wherein n^(c) is as defined above, or a salt thereof.
 44. A compound ofthe formula:


45. A method for producing a compound of the formula

wherein n^(c) is an integer of 1 to 10 and other symbols are as definedin claims 32, or a salt thereof, which comprises subjecting a compoundof the formula

wherein each symbol is as defined above, or a salt thereof tosulfonylation or halogenation, and reacting the resulting compound witha compound of the formula

wherein n^(c) is as defined above, or a salt thereof. 46.1-[4-[4-[[2-[(E)-2-[4-(Trifluoromethyl)phenyl]ethenyl]-1,3-oxazol-4-yl]methoxy]phenyl]butyl]-1H-1,2,3-triazole.47. The crystal of claim 46, having characteristic peaks at diffractionangles of 6.98, 14.02, 17.56, 21.10 and 24.70 degrees in powder X-raydiffraction.
 48. A pharmaceutical composition comprising the crystal ofclaim 46.